The key factor of genome instability during aging is transposon dysregulation. This may be due to senile changes in the expression of lamins, which epigenetically modulate transposons. Lamins directly physically interact with transposons. Epigenetic regulators such as SIRT7, BAF, and microRNA can also serve as intermediaries for their interactions. There is also an inverse regulation, since transposons are sources of miRNAs that affect lamins. We suggest that lamins can be attributed to epigenetic factors, since they are part of the NURD, interact with histone deacetylases and regulate gene expression without changing the nucleotide sequences. The role of lamins in the etiopathogenesis of premature aging syndromes may be associated with interactions with transposons. In various human cells, LINE1 is present in the heterochromatin domains of the genome associated with lamins, while SIRT7 facilitates the interaction of this retroelement with lamins. Both retroelements and the nuclear lamina play an important role in the antiviral response of organisms. This may be due to the role of lamins in protection from both viruses and transposons, since viruses and transposons are evolutionarily related. Transposable elements and lamins are secondary messengers of environmental stressors that can serve as triggers for aging and carcinogenesis. Transposons play a role in the development of cancer, while the microRNAs derived from them, participating in the etiopathogenesis of tumors, are important in human aging. Lamins have similar properties, since lamins are dysregulated in cancer, and microRNAs affecting them are involved in carcinogenesis. Changes in the expression of specif ic microRNAs were also revealedin laminopathies. Identif ication of the epigenetic mechanisms of interaction of lamins with transposons duringagingcan become the basis for the development of methods of life extension and targeted therapy of age-associatedcancer Nuclear lamina (NL) is a protein network connected to theinner side of the cell’s nuclear envelope. Nuclear laminaperforms structural, signaling and regulatory functions. Thestudy of the evolution of NL components made it possibleto discover a wide variety of domains and sequence architecturesthat go beyond the classical alpha-helices . Nuclear lamina is composed of lamins and associatedproteins . The main componentsof NL are lamins . Their genes werepresent at the earliest stages of eukaryotic evolution. Laminshave been identified in multicellular organisms, amoebas, andprimitive opistocontes such as Ichthyosporea and Choano-flagellates . Lamins are required not only tomaintain the shape of the nucleus, but also to control replicationand transcription. Lamins are proteins of the family ofintermediate filaments (class V) with a specific structure. Inmammalian cells, 4 types of lamins are expressed: A and C(splicing isoforms of one gene), B1 and B2 . Minor isoforms Аδ10 and С2 are also known. Theprotein precursor of lamin A is prelamin A. Its C-terminalregion is post-translationally modified: farnesylated, carboxymethylated.Proteolysis of the CaaX motif of pre-laminA also occurs using the metalloprotease ZMPSTE24. Lamins A, С, Аδ10 and С2 are encodedby LMNA gene .Proteins that interact with lamins and are closely associatedwith them functionally include LBR (lamin B receptor),BAF (barrier to autointegration factor), SUN1, SUN2,nesprin. They are involved in the structural organization ofthe nucleus and in the regulation of nuclear processes. LBRand endoprotease prelamin A have enzymatic properties.At the periphery of the nucleus, genomic DNA binds tolamins A and B, forming heterochromatic domains. Lamin Aalso binds to chromatin inside the nucleus – the nucleoplasmicenvironment is represented mainly by euchromatin,which indicates the role of lamin A in the regulation ofgene expression of the entire genome .Lamin B interacts with genomic domains that are relativelygene-poor and transcriptionally inactive . It is assumed that in the last common predecessor ofall eukaryotes (LECA – last eukaryotic common ancestor),the configurations of the nuclear envelope and the associatedNL played an important role in determining the activity ofthe nucleus.In the subsequent evolution, there were changes in themechanisms of regulation of gene expression of lamins indifferent taxa. The protein diversity of lamins in plants andtrypanosomes is taxonomically limited, while in multicellularanimals it is manifested in a wider range. The phylogenetictree of lamina genes is characterized by verticalevolution. For example, two lamins in protists from stronglydiverging taxa have targets in mammalian cell nuclei andpolymerize into filamentous structures, which indicates thefunctional preservation of distant homologues of lamins.In certain groups of eukaryotes, a pronounced evolutionaryplasticity of the structures of the NL was determined by themechanisms of chromatin binding and epigenetic controldue to a high level of divergence of lamins’ homologues.Lamin changes occur with aging and in age-associateddiseases such as malignant neoplasms. For example, in lungcancer, significant reductions in lamin B1 levels are found. Lamin A regulates the activity ofmTOR (mechanistic target of rapamycin), the low activityof which contributes to an increase in life expectancy.Inhibition of mTOR  leadsto the degradation of defective molecules and organellesthat accumulate in cells during aging, since low autophagyactivity is a characteristic feature of aging-related diseases.Lamins can be attributed to epigenetic factors, since theyensure the inheritance of the functional status of the gene.For example, the attachment of lamin B1 to specific genomeloci leads to transcription suppression of genes located inthem. Most differentially expressed genes are activated dueto the loss of lamin B1. These include the genes of the REToncogene and its corepressor GFRα1. Therefore, when laminB1 is depleted with aging, the risk of tumors increases.Another mechanism of RET activation is H3K27me3 histonemethylation .Epigenetic factors include chromatin remodeling, modificationsof histones and DNA nucleotides, and the influenceof non-coding RNAs (ncRNAs). During cellular senescencein mammals, H3K56ac and H4K16ac levels decrease, whichcontributes to altered gene expression, genomic instability,and telomere damage. Aging is accompanied by a globaldecrease in DNA methylation levels, coinciding with agerelatedloss of heterochromatin. As a result, the regulationof gene expression and activation of transposable elements(ТЕs) is disrupted. At the same time, the participation oflamins in epigenetic regulation associated with aging occurs through direct interaction with chromatin in regions ofspecific DNA sequences called lamin-associated domains(LADs).Lamins also promote epigenetic changes during agingthrough functional interactions with sirtuins. For example,lamin A enhances the deacetylase activity of SIRT1, stimulatesthe functioning of SIRT6 in DNA repair, and recruitshistone deacetylase 2 (HDAC2). Lamins A/C are also directparticipants in epigenetic regulation, since they serveas components of the NURD (nucleosome remodelingdeacetylase complex). This complex also includes HDAC1,RBBP4, RBBP7 . Lamins A/C interactwith histone deacetylase 2 (HDAC2) and with PCAF acetyltransferase(p300-CBP associated factor) . Lamin B1 recruits the PRC2 (Polycomb repressivecomplex 2) complex, through which the H3K27me3 landscapechanges with repression of specific genes involved insignaling and cell migration .The development of progeria in patients with germinalmutations in the genes of lamins proves the role of laminsin regulation of life expectancy. Progeroid laminopathies(PLs) are characterized by premature aging and death fromcomplications of atherosclerosis such as myocardial infarction,stroke, or heart failure. PLs are usually not inheritedbecause patients do not survive to puberty.An important genetic feature of progeria is telomereshortening with each replication cycle .The most famous of these diseases is Hutchinson–Guildfordprogeria (HGP), which is characterized by significant telomereshortening. The disease is diagnosed from two yearsof age, when noticeable symptoms of premature aging aredetermined. Life expectancy in HGP patients is 10–20 years.In 90 % of HGP patients, mutations in the LMNA gene aredetermined . The frequency of occurrenceof HGP is 1 in 8 million newborns .The most common mutation in LMNA gene is C1824T,which leads to accumulation of progerin (the dominantnegative form of lamin A).Interestingly, progerin also accumulates in cells duringphysiological aging as one of the rare splicing forms oflamin A transcripts. However, in comparison with physiologicalaging, more severe epigenetic changes occur inHGP, such as covalent modifications of histones with atendency to loss of separation into hetero- and euchromatin.These epigenetic changes lead to changes in the spatialcompartmentalization and conformation of chromatin inthe nucleus. These processes involve microRNAs, such asmiR-9, which can be used as a target for brain protection inHGP patients . MiR-9 interacts withthe 3′-untranslated region (UTR) of lamin A mRNA withoutaffecting lamin C. 3′-UTR region of prelamin A contains anadditional binding site for miR-9. In experiments on miceand human HeLa cell cultures, it was proved that miR-9expression significantly reduces the levels of lamin A .As with normal aging, abnormal accumulation of progerinsuppresses the interactions of lamin A with SIRT1, HDAC2,and SIRT6. In addition, in patients with HGP, the regulationof the heterochromatin protein HP1 is impaired, the levels ofH3K9me3 decrease, and the NURD function is suppressed(of which lamin A/C is a component). At the same time, therelationship of lamin A/C with HDAC2 causes the activationof the CDKN1A gene, which is the most important determinantof cellular senescence .Mutations in LMNA gene also cause atypical Werner’ssyndrome (AWS), mandibuloacral dysplasia type A (MADA),atypical progeria syndrome (APS) . Theydiffer in disease-specific mutations in LMNA gene and inclinical manifestations. Dunnigan-type familial partiallipodystrophy is caused by an R482W missense mutationin lamin A, leading to a pathological change in its effect onthe periphery and inside the nucleus on a three-dimensionalrearrangement of chromatin . MADAcan be caused by mutations in the LMNA or ZMPSTE24genes. It is a rare autosomal recessive disorder characterizedby bone abnormalities with localized osteolysis and generalizedosteoporosis, skin pigmentation, lipodystrophy, andaccelerated aging. These mutations cause accumulation ofprelamin A, which leads to disruption of chromatin dynamics.Similar changes are found during physiological aging.Progeroid laminopathies are also caused by mutationsin genes that interact with lamins. For example, Nestor–Guillermo progeria (NGPS) is caused by mutations in theBAF gene . Premature aging syndromescan be caused not only by mutations in the genes of laminsand proteins interacting with them, but also by mutationsin the genes of DNA repair and maintenance enzymes. Forexample, mutations in helicase genes cause Rothmund–Thomson syndrome (RECQL4 gene), Bloom syndrome(BLM gene), Werner syndrome (WRN gene). Mutations inDNA repair genes cause Dyskeratosis congentia  and Cockayne syndrome (ERCC8 orERCC6 genes). In contrast to these premature aging syndromes,PLs are characterizedby an early onset, more severemanifestations of aging and a lack of predisposition to cancer. All PLs are characterized by generalizedosteoporosis and osteolysis, crowding of teeth with malocclusion.Progeroid laminopathies with a specific lesion ofthe musculoskeletal system include heart-hand syndromeof Slovenian (HHS-S) . Mutationsin the ZMPSTE24 gene are causes of the development ofrestrictive dermopathy (RD) and mandibuloacral dysplasiatype B (MADB) .In ataxia-telangiectasia patients, accumulation of laminB1 causes changes in the shape of the nucleus and cellaging. Oxidative stress in this syndrome increases lamin B1levels by stimulating mitogen-activated protein kinase p38(p38 MAPK). In cell experiments using the MAPK activatoranisomycin and the MAPK inhibitor SB203580 todetermine the effect of p38 MAPK on lamin B1 levels,p38 MAPK activation was shown to significantly increase lamin B1 levels. At the same time, inhibition of p38 MAPKdecreases lamin B1 levels. Using the PLA method (proximityligation assay), it was proved that p38 MAPK interactswith lamin B1, causing its phosphorylation . These changes also occur during natural aging. Also,PLs are characterized by decrease in perinuclear heterochromatinand increase in cellular senescence – two conditionsthat correlate with dysregulation of TEs . It can be assumed that in evolution, lamins arose asone of the protective mechanisms aimed at silencing TEsto protect hosts from genomic instability . Therefore, laminopathies that cause premature agingand aging-associated pathology are most likely to cause activationof TEs as a key mechanism for the development ofdiseases . Indeed, in an experimenton cell models expressing progerin characteristic of HGP,a pronounced increase in the expression of LINE, SINE,HERV and DNA transposons was revealed .Transposable elements are elements capable of transpositionwithin the genome. There are two classes of TEs: retroelements(REs), transposed by reverse transcription andintermediate RNA; DNA-TEs, transposed using transposaseby the mechanism of excision and insertion . All TEs are subdivided into autonomous (containgenes of transposition enzymes) and non-autonomous (useprotein products of other TEs for their transpositons). Retroelementsare classified into those containing LTR  – LTR-REs and non-LTR-REs. The mostcommon autonomous non-LTR-REs in the human genomeare LINE1 (long interspersed nuclear elements), and nonautonomousones are SINE .LTR-REs includes human endogenous retroviruses(HERV) . Silencing of TEs is normallyensured by the degradation of their RNA and the formationof heterochromatin. Therefore, TEs are characterized byactivation during aging of organisms as a result of ageassociatedderegulation of heterochromatin and microRNA.The relationship between TEs activation and aging wasfound in termites. Reproductive queens live for tens of yearswithout a significant increase in TEs expression, while workingtermites live for only a few weeks, which is due to TEsdysregulation in their genomes due to changes in piRNAexpression . Interestingly, in the somaticcells of Cnidaria, which are characterized by almost un-limitedregeneration and immortality, piRNA and Piwi proteinsare also expressed. It is accompanied by low levels ofTEs activity in their genomes. These properties were revealedin Hydra vulgaris . Piwi homologuesnamed Cniwi are found at all stages of developmentof Podocoryne carnea not only in reproductive cells, butalso in differentiated somatic cells . Sincethe DNA repair systems in Cnidaria do not have a specificefficiency that distinguishes them from other animals, it can be assumed that the expression of piRNA in their organismsis the cause of delayed aging processes .During human aging, there is a progressive activationof LINE1, which leads to the activation of the interferonresponse due to the accumulation of LINE1 cDNA. Thesechanges are the cause of aseptic inflammation and theactivation of interferon observed during aging . At the same time, an increase in the level ofproinflammatory cytokines in myeloid immune cells in thethymus during aging is accompanied by a gradual decreasein the level of lamin B1, which specifically functions forthe correct organogenesis of the thymus by maintainingthe expression of epithelial cell genes. It was found thata decrease in the level of lamin B1 leads to an increase intranscription of 533 genes and suppression of expression of778 genes. Analysis of these genes showed their participationin cell adhesion, development of the immune system,differentiation of T-lymphocytes and cytokine production. Interestingly, chronic inflammation isalso characteristic of PLs. In this case, the STAT1-regulatedinterferon-like response is induced by DNA hybrids: RNAthrough the signaling pathways cGAS (cyclic GMP-AMPsynthase) and STING (stimulator of interferon genes) .Transposable elements are the most important sensorsof environmental stressors, exerting an adaptive regulatoryeffect on protein-coding genes . According to the theory of “buffering function ofthe tail of lamins”, NL acts as an intracellular sensor of thereactive oxygen species (through conservative changes in thecysteine residue in the tail domain of the lamin). Throughoutmammalian phylogeny, three cysteine residues  at the C-terminus of lamin A are conserved. Of these,C588 and C591 are also characteristic of other vertebrates,and C522 is absent in non-mammalian animals.Experiments on human skin fibroblasts showed that theseamino acids in the functional tail domain of lamin A increasethe sensitivity to reactive oxygen species, and their replacementwith alanine promotes cellular aging . Thus, lamins and TEs are sensors for stressors thatcan cause their dysregulation. Moreover, abnormalities inthe expression of TEs and lamins can potentiate each other,contributing to aging. Indeed, in experiments on Drosophila,the relationship between the age-related decrease in lamin Band the activation of various REs was proved .Aging can be induced not only by decreased levels oflamins, but also by their increased production . REs are also characterized by similar properties.For example, in the study of 111 known REs in young andold Drosophila, not only an increase in the expression of18 specific REs was determined, but also a decrease in thelevels of other 18 REs . That is, withaging, there is not just an activation of TEs or a decrease inthe levels of lamins, but a variety of changes in their expression,which potentiate each other.The question arises as to what is primary – dysregulationof lamins or TEs. Investigation of the relationship betweenlamins and TEs could provide a basis for identifying the keymechanisms of physiological aging and for the developmentof new ways to prolong life. It is possible that changes inthe levels of lamins and TEs expression during aging is acorrelation rather than a causal relationship; however, theavailable data on their interconnections suggest a mutualpotentiation of these structures during aging.In different cells, LINE1s in the human genome are abundantin the lamin-associated domains of heterochromatinregions at the nuclear periphery. Sirtuin SIRT7 is involvedin epigenetic transcriptional repression of LINE1 throughoutthe genome. The interaction of SIRT7 with A/C laminsplays an important role in this process. At the same time,SIRT7 provides deacetylation of H3K18, facilitating the interactionof LINE1s with NL. Deacetylation of H3K18 isinsufficient to suppress LINE1s expression in the absence oflamins A/C, and depletion of lamins leads to transcriptionalactivation of LINE1s. That is, for the repression of LINE1s,their relationship with lamins A/C is necessary .During the supercompactisation of differentiating humanneutrophils genomes, centromeres, percentromeres, andLINEs move to the NL region. This property is retained forLINE in LBR-deficient cells, but is lost for other heterochromatinregions . Human retroelementsLTR7/HERV-H, LTR5_Hs, and L1HS form specific regulatoryregions in the genome that selectively and site-specificallybind to lamin B1, as well as to NANOG homeobox,POU5F1, and CCCEC-binding factor .There is also an inverse relationship where lamin B maintainsthe integrity of the nuclear genome by repressing TEs,which was found in experiments on Drosophila . Prelamin A is interconnected with TEs throughBAF, which inhibits the integration of retroviruses. BAF isalso found in protein complexes containing Sleeping Beautytransposase . BAF is required to modulatethe effect of prelamin A on chromatin structure because itinduces histone H3K9 trimethylation, as well as nuclearrelocalization of the lamin-associated proteins LAP2-α andHP1-α .Lamins  and transposons  are sensors of environmental stresseffects, characterized by their interconnection and possiblepotentiation of dysregulation during aging. Therefore, it isnecessary to consider other possible mechanisms affectingtheir activity during aging. Environmental factors causingdysregulation of lamins and TEs include exogenous viruses.Determination of the role of lamins in viral infection canbecome the basis for identifying possible new ways of antiviraltherapy, as well as the use of viral vectors for correctingaging processes by acting on specific lamins.Induction of lamins A/C occurs in naive CD4+ T cellsupon antigen recognition. In this case, lamins A/C act as alink between the nucleus and the plasma membrane duringthe activation of T cells. In experiments on mice, the role oflamins A/C in the response to vaccinia virus was revealed. Proteins hnRNP and laminsA/C serve as carriers and mediators for the movementof p17 protein of avian reovirus between the nucleus andthe cytoplasm . The latency of HIV-1after integration is characterized by reversible silencingof transcription driven by the LTR of the HIV genome.The lamin-interacting protein SUN2 maintains repressivechromatin and inhibits the transcription of proviral DNA,which is regulated by HIV LTR through its association withlamins A/C. Lamins A/C bind SUN2 to nucleosomes andto HIV-1 5′-LTR, which causes blockages of viral initiationand elongation of transcription .The release of herpesviruses from the nucleus is accompaniedby a change in the architecture of the NL . Herpes simplex virus-1 induces phosphorylationand reorganization of lamins A/C through the virulencefactor – the product of the y134.5 gene. It allows the virusto exit through the nucleus . In turn, laminsfacilitate the access of capsid to the inner nuclear membraneand the curvature of its sections around the capsid of theherpes virus during budding .TRIM E3 ligase controls the replication of HSV-1 herpesvirusesby affecting the integrity of lamins through changesin the structure of the host cell centrosomes. TRIM43ubiquitinates the centrosome protein pericentrin, causingits proteasome degradation. It leads to lamins changes thatsuppress the active state of viral chromatin .The mechanism of this phenomenon is due to the specificinteraction of lamin A/C with the genomic DNA of the virusat the nuclear periphery. In this case, lamin inhibits the formationof heterochromatin in the region of HSV promoters.Caspase-6-dependent dephosphorylation of lamins A/Cis essential for SV40 virus penetration . Baculovirus promotes phosphorylation of lamin Band destruction of NL during infection .Canine parvovirus in the late stage of infection reorganizesNL with decreasing the levels of lamins A/C in the apicalpart of the nucleus .The interrelation of lamins with viruses may indicate thepossible participation of NL in the interconversion of viruseswith TEs, as well as in transposon-controlled regulatorynetworks of genomes. Like lamins, TEs are involved in antiviralresponse, which may be related to their phylogeneticrelationship. In the course of evolution, LTR-REs becamesources of exogenous retroviruses .ERV of various mammalian species are capable of convertinginto infectious form of viruses and converting back toREs . Expression products of LTRREsenv genes cause restriction of exogenous retrovirusesin animals . Retroelements enzymes can also be used to integrate exogenous viruses into hostgenomes . Exogenous viruses canregulate TEs activity. For example, human cytomegaloviruscauses tissue-specific activation of LTR-RE . MicroRNAs can serve as possible mediators in theinteractions of viruses with TE and lamins. Investigation ofmicroRNAs is promising both for the development of methodsfor slowing aging processes and for antiviral therapyMicroRNA are involved in regulation of lamins  and TEs. It may be due to theorigin of miRNAs in evolution from transposons. For the firsttime, evidence of the emergence of 55 different microRNAsfrom human TEs was obtained in 2007 . In 2009, 73 human microRNAs derived from TEswere identified . In 2011, 191 microRNAsthat arose from TE were identified .In the same year, another research group identified 226 humanmicroRNAs derived from TE (MDTEs) . In 2012, 235 human MDTEs were identified , 409 MDTEs were identified in 2015 , 34 MDTEs were identified in 2020. In 2016,the MDTE database was created. This database containsinformation about microRNAs originated directly from TEs.Aging is an important risk factor for the developmentof oncopathology. It may be due to common epigeneticmechanisms, since during aging, global DNA hypomethylation,TEs activation, and the development of genomicinstability occur . This assumption canbe confirmed by data on the role of the same microRNAsin both carcinogenesis and aging. A lot of information hasbeen accumulated on the association of various microRNAswith the development of tumors. Bioinformation databaseOncomiR was created (www.oncomir.org) . We analyzed 410 different microRNAs featured inOncomiR using the MDTE database . Asa result, we found that 94 of these microRNAs were derivedfrom TEs. It indicates the role of these microRNAs in thedevelopment of malignant tumors and the possibility of theiruse as a target for antitumor therapy.Like TEs, lamins also play a role in carcinogenesis. Itwas shown that a deficiency of lamins A/C can be used asan independent risk factor for the development of cervicalcancer . Lamin B1 levels are significantlyincreased in patients with hepatocellular carcinoma. Lamin B2 is highly expressed innon-small cell lung cancer and positively correlates withlymph node metastases. It is due to the interaction of laminB2 with cyclin D1, which activates G9α expressionand increases H3K9me2 levels. As a result, H3K9me2 bindsto the promoter region of the E-сadherin CDH1 gene andstimulates cell migration .In gastric cancer, lamin B1 expression is reduced intumor tissue, and low levels of lamin B1 are significantlycorrelated with clinical stage severity, depth of invasion, andpoor prognosis. In the experiment, inhibition of lamin B1causes the proliferation and migration of gastric cancer cells,which is due to the activation of the PI3K/PTEN/Akt andMAPK/ERK pathways, as well as the suppression of p53/h21WAF1/CIP1 .Low levels of lamins A/C expression in cancer are specificfor poor prognosis. In breast cancer (BC), the loss ordecrease in the expression of lamins A/C was significantlyassociated with large tumor sizes, poor prognosis and thedevelopment of long-term results . Comparison of osteosarcoma andosteoblast cell lines showed a lower level of lamin A expressionin osteosarcoma cells. Elevated lamin A levels reducecancer cells’ ability to migrate .Thus, carcinogenesis is associated both with an increaseand (most often) with a decrease in lamin expression, thatis, it is explained by their dysregulation.This is due to the global regulatory role of lamins in theexpression of various genes. Therefore, it is important todetermine the specific features of changes in the expressionof lamins in each type of tumor in order to target themduring antitumor therapy. Most tumors are characterized bydecreased lamins expression, which may be one of the keymechanisms of initiation and maintenance of carcinogenesis,because lamins serve as host defense systems for TEssilencing. Therefore, the loss of control by the lamins leadsto pathological activation of TEs with subsequent genomicinstability and tumor development. The effect of increasedlevels of lamins on tumor development is probably due tothe possibility of opposite regulatory effects of lamins onTEs, depending on localization of TEs in active or repressedgenome regions .Like transposons, during aging and carcinogenesis, laminsare also associated with changes in microRNA levels. Forexample, the target of the oncogenic miR-129, the expressionof which is increased in BC, is lamin A. The target of theoncogenic miR-218, the level of which decreases in BC, islamin B1 . LMNA expression in breastcancer cells is suppressed by miR-9, which leads to the progressionof the disease due to changes in the deformabilityof the nucleus and an increase in the invasive ability ofcells . MiR-122 inhibits hepatocellularcancer cell proliferation by suppressing the expression oflamin B2 . MiR-351-5p regulates lamin B1expression and promotes phloxuridine-induced tumor cellapoptosis . In fibroblasts associated withBC, the expression of miR-222 is increased . The direct target of this microRNA is LBR.Therefore, miR-222 is considered for BC targeted therapy.During human aging, the levels of LMNB1 protein productsin fibroblasts and keratinocytes of the skin decrease,which is mediated by the influence of miR-23a . An increase in LMNB1 expression due to geneduplication in autosomal dominant leukodystrophy in adultsleads to progressive brain demyelination. This is due to the role of lamin B1 in regulation of myelin formation and maintenanceduring aging. The targets of miR-23a are also thePTEN gene transcript (phosphatase and tensin homolog onchromosome 10) and long noncoding RNA 2700046G09Rik. MiR-124-3p complementarily binds to3′-UTR of LMNA gene, suppressing its expression . Activation of miR-141-3p during replicativesenescence decreases the activity of HDAC1 and HDAC2.MiR-141-3p has a targeted regulatory effect on ZMPSTE24endoprotease prelamin A .Like TEs, miRNAs affect lamins according to the principleof mutual regulation, since miRNAs genes are located in genomeregions associated with lamins. For example, in mice,aging-associated miRNA genes are located on the X chromosomein a cluster located in the lamin-associated domain. Long noncoding RNA Xist is involved inX chromosome inactivation by directly interacting with theLBR and recruiting it to the NL. It leads to remodeling ofthe three-dimensional structure of DNA, which allows Xistto distribute along the X chromosome and cause silencingof transcriptionally active genes .In skeletal muscles of patients with muscular dystrophiescaused by mutations in LMNA gene, pronounced dysregulationof sixteen different microRNAs was revealed, whichare involved in Wnt-signaling pathways, MAPK, and theregulation of transforming growth factor β. Nine of these microRNAsare involved in regenerative processes and are detected at high levels in fetal muscles . Expression of the mutant allele of LMNA gene(mutation R482W) is accompanied by an increase in levelsof miR-335, which has antilipogenic properties . Significantly increased expression of let-7a-5p,miR-142-3p, miR-145-5p, and miR-454-3p is observed inpatients with familial dilated cardiomyopathy associatedwith mutations in LMNA .According to the MDTE database, among the miRNAsassociated with lamina pathology, the origin from LINE2was proven for miR-192 and miR-502, the origin from MIR(SINE-RE) was proven for miR-335 . Itshould be noted that miR-335 also plays a role in humanphysiological aging and age-associated neurological pathology. It may be due to the role of laminsin protecting genomes from transpositions , since TEs are involved in the epigenetic regulationof lamins. That is, the structural and functional relationshipbetween lamins and TEs is mutually regulatory. On the onehand, lamins are involved in the control of TEs activity. Onthe other hand, TEs can exert an epigenetic regulatory effecton NL, which may be due to the influence of microRNAsderived from TEs.Lamins play an important role in driving gene expressionand in TEs silencing, thereby preventing genome instability.Therefore, dysregulation of lamins, mainly associated withinactivating mutations in their genes or a decrease in theirexpression, leads to TEs activation. Therefore, pathologicalactivation of TEs and the resulting genomic instabilityplay an important role in changing the levels of lamins inmalignant neoplasms. The role of lamins in viral infectionsupports this assumption, since TEs are phylogeneticallyassociated with viruses.Transposable elements and lamins share common properties,such as dysregulation during aging and carcinogenesis,as well as interactions with microRNAs. Mutual regulationof lamins and TEs testifies to the mutual potentiation oftheir dysregulation in laminopathies, carcinogenesis andphysiological aging. 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This blueprint is composed of a 4-letter alphabet. Together, the multiple significant changes in the blueprint then allow a cell to go “out of control”, becoming a cancer cell. The striking thing about MRT is that it has only a single spelling change, so that mutation must be very powerful to lead to such a lethal cancer. Using a model system that we developed, we show herein how this single mutation alters how the whole of the DNA is arranged, thereby having its profound and lethal effects. We present insights into how this mutation arrests maturation of the cells, keeping them in a cancer “state”.Malignant rhabdoid tumors (MRT), one of the most lethal, treatment-resistant human cancers, arises in young children within brain, kidney, liver and/or soft tissues. Generally, cancer arises in older adults, and results from Human cancer typically results from the stochastic accumulation of multiple oncogene-activating and tumor-suppressor gene-inactivating mutations. However, this process takes time and especially in the context of certain pediatric cancer, fewer but more ‘impactful’ mutations may in short order produce the full-blown cancer phenotype. This is well exemplified by the highly aggressive malignant rhabdoid tumor (MRT), where the only gene classically showing recurrent inactivation is SMARCB1, a subunit member of the BAF chromatin-remodeling complex. This is true of all three presentations of MRT including MRT of kidney (MRTK), MRT of the central nervous system  and extracranial, extrarenal rhabdoid tumor (EERT). Our reverse modeling of rhabdoid tumors with isogenic cell lines, either induced or not induced, to express SMARCB1 showed widespread differential chromatin remodeling indicative of altered BAF complex activity with ensuant histone modifications when tested by chromatin immunoprecipitation followed by sequencing (ChIP-seq). The changes due to reintroduction of SMARCB1 were preponderantly at typical enhancers with tandem BAF complex occupancy at these sites and related gene activation, as substantiated also by transcriptomic data. Indeed, for both MRTK and ATRT cells, there is evidence of an overlap between SMARCB1-dependent enhancer activation and tissue-specific lineage-determining genes. These genes are inactive in the tumor state, conceivably arresting the cells in a primitive/undifferentiated state. This epigenetic dysregulation from inactivation of a chromatin-remodeling complex subunit contributes to an improved understanding of the complex pathophysiological basis of MRT, one of the most lethal and aggressive human cancers. By accepted dogma, cancer is a multistep process requiring the stochastic accumulation of generally 5–6 mutations for the full phenotype with all the pathophysiological “hallmarks” of cancer to be expressed ,2. By viSMARCB1  gene [An earlier onset of cancer in childhood clearly defies this dogma of stochastic mutation accumulation, with malignant rhabdoid tumors (MRT) representing a remarkable example of this. This tumor of infancy, despite its lethality, bears but one recurrent gene mutation, that of bi-allelic inactivation of the A4) gene ,4,5. MRTA4) gene .SMARCB1 (or SMARCA4), defining the rhabdoid predisposition syndrome 1 or 2 , respectively [Admittedly, 35% of patients presenting with MRT have germline mutation of ectively ,8, but tSMARCB1  encodes a core protein subunit of the BAF  ATP-dependent chromatin-remodeling complex, which is involved in the energy-dependent (re)organization of chromatin through alterations in the periodicity or torsional stress, and/or histone composition of nucleosomes within the chromatin, contributing in large part to the 5000-fold compaction of DNA within the human nucleus [ nucleus ,10,11. I nucleus ,13,14,15 nucleus . In rela nucleus ,18,19. THerein we sought to establish, by reverse modeling of SMARCB1 loss through the re-introduction of SMARCB1 into malignant rhabdoid tumors cell lines representative of MRTK (G401) and ATRT (BT16), just how dysregulation of the chromatin landscape could contribute to oncogenesis. We focused on a direct comparison of otherwise isogenic cell lines with and without induced expression of SMARCB1, to establish the resultant BAF complex composition and localization, and tandem histone post-translational modifications throughout the genome, with especial reference to regulatory sequences.As lineage determination and maintenance of cell identity reflect the transcriptome and by inference, any chromatin regulation contributing to this—“cellular state is closely related to chromatin state” , we aimeSMARCB1 is a core member of the chromatin-remodeling SWI/SNF and PBAF multi-subunit complexes. Various combinatorial permutations exist that are developmental stage and tissue specific and studies have shown that subunit composition can alter gene expression programs during lineage specification and disease . We inve−33). We similarly profiled dysregulated genes in doxycycline treated G401 cells, to find that 29% (805/2730) of the upregulated genes and 21% (445/2133) of the downregulated genes were significantly associated with SMARCB1-activated enhancers (hypergeometric test 9.8 × 10−76). SMARCB1-dependent enhancers significantly associated not only with SMARCB1-activated genes  but also with SMARCB1-suppressed genes , implying that SMARCB1 can remodel chromatin and facilitate the binding of both transcriptional activators and repressors. Nevertheless, the average fold change of the upregulated transcripts was significantly higher than that of the downregulated ones  and active promoters and enhancers (H3K4me1). 2303 (12.7%) and 600 (8%) of the gained H3K27ac peaks overlapped H3K4me3 in BT16 and G401s, respectively, all consistent with activated promoters, whereas a larger fraction of gained H3K27ac peaks, 17,747 (87.3%) and 8344 (92%) in BT16 and G401s, respectively, overlapped H3K4me1 without H3K4me3, consistent with activated enhancers. While we did observe greater H3K27ac signals at promoters upon reintroduction of SMARCB1, we did not observe a concomitant change in the level of H3K4me3, which was strong in both mock- and doxycycline-treated cells, suggesting that H3K4me3 deposition is independent of SMARCB1 at this subset of promoter peaks. Enhancer regions on the other hand were strongly positive for H3K4me1 in tandem with gained H3K27ac in the doxycycline-treated cells A,B. Thested ones C–F, suggGiven that mock-treated G401 and BT16 cells, respectively, model the cancerous state of MRTK and ATRT, we reasoned that the cells of these primitive undifferentiated tumors might lack tissue-specific regulatory cues necessary for lineage specification and terminal differentiation. To test this, we first examined clusters of narrowly spaced enhancers, called stretch- or superenhancers (SEs), in mock- and doxycycline-treated cells. SEs are linked to cell type-specific gene expression and newly acquired super-enhancers at oncogenes can lead to tumorigenesis . FollowiInterestingly, we identified 122 regions that are both gained in SMARCB1 re-expressing BT16 cells and classified as brain-specific regulatory elements  by TiED  and 146 To study the effect of SMARCB1 re-expression on BAF complex composition and genome-wide occupancy, we targeted core subunits , SWI/SNF , PBAF  and ncBAF (BRD9) ,28 subunDox-gained SWI/SNF targets, both proportionally and absolutely, far outnumbered gained-PBAF or -ncBAF targets, suggesting overall that SMARCB1 loss of function has a particularly profound effect on SWI/SNF occupancy, and particularly so at enhancers A,B.Next, we overlapped these gained SWI/SNF, PBAF or ncBAF peaks with SMARCB1-dependent H3K27Ac peaks to identify regulatory regions that are active and occupied by chromatin remodelers in SMARCB1 re-expressing cells. We focused on the top 10% of SMARCB1-dependent H3K27ac peaks in doxycycline-treated cells . In BT16 cells, the gained SWI/SNF peaks overlapped 54% of SMARCB1-activated elements. In G401s, a lower fraction (21%) of SMARCB1-activated elements were occupied by gained SWI/SNF peaks, however similarly to BT16, it was SWI/SNF predominantly rather than PBAF that showed a dox-gained occupancy at these sites C,D. ExamThese aggregate results suggest that SMARCB1, as a fundamental subunit of the SWI/SNF complex, is a major contributor to the targeted activation of distal enhancers in both BT16 and G401 cell lines.Given that rhabdoid tumor cell lines are susceptible to BRD9 inhibition ,31, we sCDK11A, CDK11B, CCND1 and VEGFA are shown in CDK11A and CDK11B, whereas only BRG1/BRD9 peaks were identified at the promoters of CCND1 and VEGFA in BT16 and G401 cell lines.Given the exquisite sensitivity of SMARCB1-deficient cells to BRD9 inhibition ,31, we hDNA methylation at CpG islands is an important regulator of gene expression. Due to CG suppression (where cytosine is spontaneously converted to thymine), CpG islands are selectively found at promoters. In fact, in humans approximately 70% of promoters contain a CpG island . MethylaWhile cancer genetic research has focused very extensively on the exome over recent decades, given that mutations within coding sequence may clearly impact significantly on the protein products of these genes to contribute to oncogenesis, it has emerged more recently that dysregulation at an epigenetic level, resulting for example from mutation in subunits of the BAF complex, may in fact contribute considerably to cancer development as well as progression ,38,39,40Hox gene repression is maintained by Polycomb group proteins (PcGs) while the BAF complex promotes Hox gene activation, in a dynamic and mutually antagonistic fashion [The importance of the BAF complex in development/differentiation has long been recognized in Drosophila, where  fashion ,48,49,50 fashion ,50 havin fashion ,51, wher fashion . This is fashion  and wher fashion ,53 but w fashion ,24. Seve fashion ,56,57,58 fashion . BAF180, fashion . Interes fashion .Most BAF subunits can bind DNA; bromodomains within ATPases bind acetylated histone lysines, chromodomains of BAF155 and BAF170 have affinity for methylated histones, not to mention the recruitment of BAF by transcription factor binding . ImportaEarly investigations of malignant rhabdoid tumors showed that re-expression of SMARCB1 led to activation of transcription initiation either by recruitment of BAF complexes or activation of existing ones, implying that oncogenesis in the context of SMARCB1 loss is due to promoter pausing . Genome-Although enhancers are key to cell fate determination, superenhancers are considered crucial notably in the regulation of master oncogenes, but no significant findings emerged from our data in terms of superenhancers specific to ‘mock-treated’ MRT cells that are then ‘lost’ with re-expression of SMARCB1 and which might thereby elucidate oncogenes specifically important to MRT establishment and survival. Some insights into the ability of the cancer cell (modeled here with the mock-treated cell lines) to survive and proliferate—starkly contrasted by the cellular senescence within few days following SMARCB1 rescue—came instead from our investigation into the role of ncBAF subunit BRD9 in the mock-treated cells. In the absence of SMARCB1, relatively larger proportions of BRG1 are incorporated into PBAF and ncBAF complexes than in the presence of SMARCB1. ncBAF complex, characterized by BRD9 amongst other subunits, has been reported to localize to CTCF and promoter loci . This waWe show herein overlaps between activation and tissue specificity of enhancers for both cell lines. Indeed, amongst top tissue specificity of doxycycline-gained enhancers for G401 and BT16 cell lines are kidney and brain, respectively. Furthermore, analysis of DNA methylation in tissue samples from normal kidney and from malignant rhabdoid tumors of kidney reveals evidence of suppression of renal differentiation-associated genes in MRTK and by contrast, silencing of ‘alternative’ differentiation lineages in normal kidney tissue at promoter CpG islands, the bona fide epigenetic mechanism of gene silencing. Taken together, these observations support our contention that failure of differentiation underpins the oncogenic process in MRT development.SMARCB1 following a previously published protocol [SMARCB1 was amplified from normal kidney tissue and cloned with HA-tag into a doxycycline/tetracycline-inducible pLVX Tight Puro lentiviral  expression system. Cells were transfected with viral packaging vector Pax2, envelope vector MD2G, and pLVX Tight Puro containing HA-SMARCB1 using Lipofectamine 2000 . The optimum dose of doxycycline to induce HA-SMARCB1 expression was determined as 0.1 ng/μL. SMARCB1 protein expression was verified by Western blot analysis prior to each experiment.The G401 and BT16 cell lines were stably transfected with doxycycline-inducible HA-tagged protocol  with ming, cell pellets were washed twice in PBS and crosslinked as described below.Normal kidney tissue samples were identified by a consultant pathologist, retrieved fresh and snap-frozen and stored at −80 °C without delay following nephrectomy for tumor resection. Samples were anonymized and had been obtained with patient/parental consent providing for use in biological studies. A relevant application passed through the Medical Research Ethics Committee of Children’s Health Ireland at Crumlin where approval was granted. Snap frozen kidney tissue (0.1 g) was cut into small pieces using a sterile surgical scalpel. Cut tissue was transferred to 15 mL tubes containing ice-cold PBS. The cut tissue was homogenized using a TissueRuptor II . Cells were centrifuged for 5 min at 600× 3, and 1% SDS) containing protease inhibitors . Cells were snap-frozen in liquid nitrogen and stored at −80 °C for later use.Standard one-step crosslinking was performed when targeting histone post-translational modifications  for ChIP-sequencing. G401 and BT16 HA-SMARCB1 cells were cultured in T75 flasks  and treated with 0.01 ng/uL doxycycline or DMSO (mock treatment) for 72 h. The cell monolayer or homogenized kidney tissue was washed twice with pre-warmed PBS. Cells were incubated at room temperature in 1% formaldehyde (FA) solution  for 10 min before adding 0.125 M glycine (Millipore Sigma) to quench the crosslinking reaction. Two-step crosslinking  was perf3, 5% Triton X-100; Millipore Sigma). Cell lysates were sonicated to obtain chromatin fragments ranging from 100 to 300 base pairs (bp). The sonicator  was set to 55% power, with alternating time intervals of 30 s “ON” and 30 s “OFF” for a total of 20 min “ON” time for FA crosslinked cells (one-step) or a total of 40 min “ON” time for cells dual crosslinked with DSG and FA (two-step). To verify optimum DNA size fragmentation and concentration, phenol/chloroform DNA extraction and ethanol precipitation were performed (see section below), and purified DNA was run on a 1% agarose gel (Millipore Sigma). The 50–70 μg/mL of cell lysate was transferred into 1.5 mL tubes  and centrifuged at 14,000× g for 30 min. Debris-free lysate was transferred to 1.5 mL safe-lock tubes (Eppendorf), 1% of the lysate was set aside for input control and the remaining lysate was immunoprecipitated overnight at 4 °C with antibodies: BAF170 , BAF155 , BRG1 , SS18 , SS18L , ARID1A , BRD9 , BAF180 , ARID2 , BRD7, HA-tag , H3K27Me3 , IgG , H3K4me1 . Immune-complexes were incubated with 70–100 μL pre-washed protein A or G Dynabeads (Invitrogen) on a rotator for 4 h at room temperature or overnight at 4 °C. Beads were washed with 1 mL of the following buffers for 5 min at 4 °C: Mixed Micelle Buffer (3 times), Buffer 500 (2 times) and LiCl Detergent Wash Buffer (2 times). The last wash was performed in TE buffer for 2 min at 4 °C. ChIP elution buffer  was added to the beads and incubated at 65 °C for 1 h. The beads were pelleted on a magnetic rack and the supernatant was incubated overnight at 65 °C to reverse the crosslinking. The eluate was phenol/chloroform extracted and ethanol precipitated. The DNA pellet was resuspended in 30–50 μL TE buffer  and transferred to a new Lo-Bind 1.5 mL tube, and stored at −20 °C.Cell lysates were re-suspended in ice-cold nuclear lysis immunoprecipitation (NIP) buffer containing two volumes of SDS lysis buffer and one volume of dilution buffer  and 2 μL glycogen (Millipore Sigma) was added. DNA was precipitated at −80 °C for 30 min and pelleted by centrifugation at 14,000× g for 20 min. Contaminants were removed with 80% ethanol and the DNA pellet was dried using a vacuum concentrator (Thermo Savant DNA 110 SpeedyVac). DNA pellets were re-suspended in TE buffer.Sonicated and input DNA was RNase  and Phosphatase K  treated for 20 min at 37 °C and for 1 h at 55 °C, respectively. DNA was diluted in TE buffer and one volume of phenol/chloroform (Invitrogen) was added. Samples were vortexed and centrifuged for 10 min at 14,000× ® 2.0 Fluorometer (Thermo Fisher Scientific). ChIP libraries were prepared from 10 ng DNA using the NEBNext®Ultra-library preparation kit for Illumina  with Dual indexing NEBNext® Multiplex Oligos  following the manufacturer’s protocol. DNA libraries were purified and size selected (200–500 base pairs) by two rounds of AMPure bead purification. Library fragment length was validated using the High Sensitivity (HS) ScreenTape for 2200 TapeStation . ChIP library amplification was validated by qPCR at a set of known positive and negative control genes.Before library preparation and sequencing, all antibodies were first screened for ChIP-grade potential in SMARCB1-expressing cells by ChIP-qPCR. We considered antibodies suitable for ChIP-seq when target enrichment at positive control genes was 10-fold greater than IgG background signal at the same loci  This involves running the MACS2 sub commands predictd, callpeak, and bdgdiff. This results in three sets of regions, either specific to one or the other sample, or common to both. To filter out irrelevant differential binding, we then filtered the determined regions by intersecting with the summits of peaks called by MACS2. For generation of heatmaps, the deepTools package (version 3.3.0) [http://mitra.stanford.edu/kundaje/akundaje/release/blacklists/hg19-human/ (accessed 9 November 2018) to exclude problematic regions. Plots of heat maps were generated through the ‘plotHeatmap’ command . The Homer software (version 4.10) was used to detect superenhancers and annotate peak regions. Homer “findMotifsGenome” was used to identify enriched transcription factor binding motifs from input bed files. Bedtools [Paired-end FastQ files were downloaded from the sequencing facility’s website and processed through FastQC  for qualn 3.3.0)  was usedBedtools  was usedn = 2915) and brain-specific enhancers (n = 3637) were identified as overlapping H3K27ac and H3K4me1 peaks unique to kidney tissue and absent from the other 9 tissue types.Enhancer regions from 10 unrelated tissues  were downloaded together with tissue annotation from the tissue-specific enhancer database, TiED . TiED kihttps://genome.ucsc.edu/cgi-bin/hgLiftOver, accessed on 15 March 2021). The tool annotatePeaks.pl from the Homer package was applied to assign the nearest gene to each probe.The signal intensities for dataset GSE44847, which was generated with the Illumina HumanMethylation27 BeadChip, were downloaded from Gene Expression Omnibus. For each probe an M-value was calculated by transferring the ratio of methylated vs. unmethylated signal into log2 space. We used three replicates each of samples labelled as ‘rhabdoid tumors of the kidney’ (RTK) and ‘non-neoplastic kidney’ (NK), and merged them via the mean average. The merged M-values of RTK and NK were plotted against each other using ggplot2 functions in R. Probes with high M-value in RTK samples and low M-value in NK samples were filtered and annotated. To do this, the bead locations were extracted from GEO accession GPL8490 and transferred from hg18 to hg19 using UCSC’s LiftOver tool (To correlate methylation data with gene expression, RNA-seq read counts for rhabdoid tumor and matched normal kidney samples were downloaded from the NCBI’s TARGET website . Only geRNA-seq data for G401 were downloaded in the form of read counts from GEO series GSE90633. We used two replicates each of samples labelled ‘G401_Empty_Day3′ and ‘G401_BAF47_Day3′. For BT16, three replicates each of samples labelled ‘BT16_NoDox’ and ‘BT16_Dox’ were downloaded from GEO series GSE71505 ,24. DiffWe propose that the observed apparent redundancy in epigenetic silencing through both histone/chromatin modification as well as promoter DNA methylation serves to provide credence to our theory of MRTK representing a classic example wherein an aggressive primitive cancer results from dysregulated proliferation coupled with arrested differentiation.


The vascular endothelium comprises the interface between the circulation and the vessel wall and, as such, is under the dynamic regulation of vascular signalling, nutrients, and hypoxia. Understanding the molecular drivers behind endothelial cell (EC) and vascular smooth muscle cell (VSMC) function and dysfunction remains a pivotal task for further clinical progress in tackling vascular disease. A newly emerging era in vascular biology with landmark deep sequencing approaches has provided us with the means to profile diverse layers of transcriptional regulation at a single cell, chromatin, and epigenetic level. This review describes the roles of major vascular long non-coding RNA (lncRNAs) in the epigenetic regulation of EC and VSMC function and discusses the recent progress in their discovery, detection, and functional characterisation. We summarise new findings regarding lncRNA-mediated epigenetic mechanisms—often regulated by hypoxia—within the vascular endothelium and smooth muscle to control vascular homeostasis in health and disease. Furthermore, we outline novel molecular techniques being used in the field to delineate the lncRNA subcellular localisation and interaction with proteins to unravel their biological roles in the epigenetic regulation of vascular genes. The vascular endothelium comprises the layer of endothelial cells (ECs) that create the interface between the circulation and the vessel wall that is under dynamic regulation in accordance with its environment to maintain perfusion and the supply of oxygen and nutrients required for cellular metabolism ,2. A heahttps://github.com/ENCODE-DCC/encoded/releases/tag/v121.0, accessed on 4 May 2021), there is now NONCODE , an integrated knowledge database dedicated especially to lncRNAs . Som. Som6]. Further examples of lncRNA-mediated epigenetic regulation in vascular cells, including those interacting with one of the major transcriptional repressors, polycomb repressive complex 2 (PRC2), are discussed below.eNOS, thus worsening outcomes in ischaemia, and similarly halts the endothelial lineage commitment in pro-angiogenic haematopoietic and endothelial progenitor cells . Th. Th57]. or cells ,48,59.It is now recognised that in addition to its chromatin binding capacity, PRC2 displays a tissue-specific lncRNA-binding capacity, including an ability to bind lncRNAs involved in vascular endothelial homeostasis such as MEG3—elucidating a model for PRC2 recruitment to specific loci. Both EZH2 and SUZ12 subunits bind lncRNA through conserved sequences and interact with chromatin in a mutually antagonistic fashion, with subsequent lncRNA-mediated target gene recognition through triplex formation—representing a general mechanism to guide transcriptional regulators . As wellThe use of novel technologies has immensely improved the detection of lncRNAs and the identification of their in vivo targets . ChromatIn MEG3 knock-out mice showing enhanced angiogenesis in the brain and the augmented expression of pro-angiogenic genes [Maternally expressed gene 3 (MEG3) is a major hypoxia-sensitive lncRNA which interacts with PRC2 and has complex roles in EC function. Hypoxia-inducible factor 1α (HIF1α) upregulates the MEG3 expression in response to hypoxia  and undeic genes . MEG3 isic genes . It has ic genes . Indeed,ic genes .klotho expression. Such research not only demonstrates the role of MALAT1 in devising the chromatin status of klotho but implies the prospect of targeting MALAT1 to ameliorate glomerular EC function in hyperglycaemia to impede the progression of diabetic nephropathy. LncRNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in the development of diabetic nephropathy through its epigenetic regulation of renal glomerular EC (HRGEC) gene expression . It was SM22a and improving aortic performance in mice [Malat1 or Hdac9 disruption restored a contractile phenotype, ameliorated aortic wall architecture, and prevented experimental TAA growth [Epigenetic pathways regulated by MALAT1 are also implicated in the development of thoracic aortic aneurysm (TAA) and stenotic disease. The dysfunction of the vascular smooth muscle cell (VSMC) through deficiencies in contractile proteins predisposes to the pathogenesis of these conditions. Histone deacetylase complex, HDAC9, is known to recruit EZH2 to epigenetically modify chromatin through the deposition of repressive H3K27me3. EZH2 was identified as a crucial player in TAA development, with its inhibition-enhancing expression of contractile protein genes such as  in mice . MoreoveA growth . MALAT1-A growth . NEAT1 knockout (KO) mice displayed decreased neointima formation and vascular repair. Moreover, ChIP assays showed that NEAT1 KO in HCASMCs enriched active chromatin marks (H3K4me3 and H3K9ac) and depleted inactive modifications [Although nuclear enriched abundant transcript 1 (NEAT1) is nuclear lncRNA, the findings have shown that its localisation is dispersed within the nucleus and is necessary for the formation of paraspeckles . Ahmed eications . MechaniANXA4) that acts as an important regulator of angiogenic sprouting and alignment of ECs [Macaca fascicularis under an atherosclerosis regression diet, and in endothelial cells isolated from human glioblastoma patients. Knocking out MANTIS with LNA-GapmeRs led to the downregulation of key endothelial genes important for angiogenesis including SOX18, SMAD6, and COUP-TFII, and the upregulation of stress-induced genes contributory to atherosclerosis such as interleukin 6 (IL-6) and superoxide dismutase 2 (SOD2). Genes in proximity to the MANTIS locus in the genome were not influenced by the MANTIS knockout, suggesting that it acts in a trans- rather than cis-regulatory manner. Mechanistically, MANTIS appears to influence epigenetic gene regulation through acting via the BRG1 component of the chromatin remodelling complex, SWI/SNF (SWItch/Sucrose non-fermentable), to facilitate access by RNA polymerase II machinery to the specific genes which counteract atherosclerotic processes [MANTIS is an intronic lncRNA-located antisense to Annexin A4  2 and 4 transcription factors [MANTIS appears to further impede atherosclerosis development by limiting pro-inflammatory intercellular adhesion molecule 1 (ICAM-1)-mediated endothelial monocyte adhesion by diminishing binding of BRG1 at the  factors . Since MeNOS expression and endothelial barrier function [eNOS promoter in ECs, acting as a facilitator of RNA polymerase II recruitment to the eNOS promoter to enhance its transcription. LEENE RNA alone was not sufficient to enhance the eNOS transcription, yet genomic or transcriptional inhibition of the LEENE enhancer region suppressed the eNOS transcription and increased the transcription of pro-inflammatory and pro-atherosclerotic ICAM1 and VCAM1 [LncRNA that enhances eNOS expression (LEENE) is an enhancer-associated RNA that plays an important role in regulating function ,34. Likend VCAM1 . Moreovend VCAM1 . LASSIE nd VCAM1 .periostin and cyclooxygenase-1. Since GATA6-AS silencing reduced H3K4me3 of genes, this suggested that lncRNA GATA6-AS negatively regulates LOXL2 the demethylase function—promoting H3K4me3 mark deposition and the activation of angiogenesis-related genes.It has previously been shown that HIF1α-dependent signalling pathways promote the hypoxia-induced, pathology-associated cellular process of endothelial–mesenchymal transition (endMT) through mediating epigenetic changes via methyltransferases in endothelial cells . Since a−/− mouse models of atherosclerosis and promoted the reversal by macrophage reverse cholesterol transport (mRCT)—suggesting a potential therapeutic modality in targeting ANRIL for treating atherosclerosis. Studies are increasingly revealing the implication of lncRNA-mediated histone methylation in the progression of atherosclerosis. LncRNA-ANRIL (antisense ncRNA in the INK4 locus), otherwise known as cyclin-dependent kinase inhibitor 2B antisense transcript 1 (CDKN2B-AS1), is known to contribute to atherosclerotic disease states including stroke, coronary heart disease, and peripheral vascular disease through epigenetically regulating the endothelial inflammatory response as well as cell proliferation, adhesion, and apoptosis . ANRIL pOur evolving understanding of lncRNAs and their role in epigenetic regulation of vascular cells may have a profound translational impact. Epigenetic therapies have already shown therapeutic potential in the context of cancer and PRC2 inhibitor agents such as EED226, EPZ, CPI-1205, and GSK126, which have also shown effectiveness in other settings. EZH2 inhibition led to the increased expression of pro-angiogenic genes and enhanced angiogenic functions and EC proliferation in vitro, whilst promoting blood flow recovery in mouse ischaemic muscles in vivo . In a moSMN gene, increasing its expression [Previously, when designing such PRC2 inhibitors, the RNA binding capacity of PRC2 was not taken into consideration. Disruption of lncRNA-mediated PRC2 recruitment has, however, been shown to reduce the severity of spinal muscular atrophy due to reduced H3K27me3 occupancy at the pression . Moreovepression . New thepression .Publications are increasingly noting the potential for lncRNA therapeutics in cardiovascular disease, with multiple vascular lncRNAs being identified as promising targets for the inhibition by antisense oligonucleotides and short hairpin RNAs in the treatment of atherosclerotic disease and in the induction of angiogenesis and vascular remodelling and repair ,80. In vRNA molecules are an attractive therapeutic concept due to their low immunogenicity, effective cell and nuclear penetration, low cost to manufacture, and ease of chemical modification . MultiplThus far, the advancements in research methods have significantly contributed to our understanding of lncRNA actions within the vasculature. Increasingly effective and sophisticated mechanistic studies are providing insight into the molecular mechanisms by which lncRNAs epigenetically regulate endothelial and VSMC gene expression in vascular homeostasis, ultimately enabling a more profound understanding of the pathological mechanisms involved in vascular disease and elucidating the potential therapeutic targets. The modulation of gene expression via targeting the epigenetic pathways implicated in angiogenesis, endothelial dysfunction, and vascular disease is a novel therapeutic avenue to explore in the future—however, greater characterisation of lncRNA interactions with the vascular gene promoters and epigenetic regulators such as PRC2 are required. Further advancements in the field largely depend on a better understanding of the structural organisation of lncRNAs and structure-to-function relations. Due to the poor conservation across species, the currently available tools for functional prediction based on a primary sequence similarity or structural predictions are not of great use . However


Background: Ankylosing Spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex aetiology and high heritability, involving more than 100 genetic associations. These include several AS-associated single nucleotide polymorphisms (SNPs) upstream of RUNX3, which encodes the multifunctional RUNT-related transcription factor (TF) 3. The lead associated SNP rs6600247 (p = 2.6 × 10−15) lies ∼13kb upstream of the RUNX3 promoter adjacent to a c-MYC TF binding-site. The effect of rs6600247 genotype on DNA binding and chromosome looping were investigated by electrophoretic mobility gel shift assays (EMSA), Western blotting-EMSA (WEMSA) and Chromosome Conformation Capture (3C).Results: Interrogation of ENCODE published data showed open chromatin in the region overlapping rs6600247 in primary human CD14+ monocytes, in contrast to the Jurkat T cell line or primary human T-cells. The rs6600247 AS-risk allele is predicted to specifically disrupt a c-MYC binding-site. Using a 50bp DNA probe spanning rs6600247 we consistently observed reduced binding to the AS-risk “C” allele of both purified c-MYC protein and nuclear extracts (NE) from monocyte-like U937 cells. WEMSA on U937 NE and purified c-MYC protein confirmed these differences . 3C experiments demonstrated negligible interaction between the region encompassing rs6600247 and the RUNX3 promoter. A stronger interaction frequency was demonstrated between the RUNX3 promoter and the previously characterised AS-associated SNP rs4648889.Conclusion: The lead SNP rs6600247, located in an enhancer-like region upstream of the RUNX3 promoter, modulates c-MYC binding. However, the region encompassing rs6600247 has rather limited physical interaction with the promoter of RUNX3. In contrast a clear chromatin looping event between the region encompassing rs4648889 and the RUNX3 promoter was observed. These data provide further evidence for complexity in the regulatory elements upstream of the RUNX3 promoter and the involvement of RUNX3 transcriptional regulation in AS. RUNX3 (Runt-related transcription factor (TF) 3) locus. RUNX3 is involved in T-cell function and plays a key role in the development of CD8+ T-cells (RUNX3 affect the binding of different factors: in particular the repressive nucleosome remodelling and deacetylase (NuRD) complex binds preferentially to the risk allele, while conversely interferon regulatory factor (IRF) five to the protective allele . Second, we demonstrate differential allelic binding of rs6600247 to the c-MYC TF. Finally, we investigate the chromosomal architecture and physical interactions between AS-associated sequences in the enhancer-like region upstream of RUNX3 and its promoter, showing a probable role of chromosome looping in the regulation of RUNX3.Ankylosing Spondylitis (AS) is a form of inflammatory spondyloarthritis predominantly affecting the axial skeleton, which is characterised pathologically by enthesitis . Extra-s T-cells . It also T-cells . We havee allele . However × 10−15  that arers6600247 using TaqMan SNP assay , for the cells (obtained by the buffy coat) used in the functional studies.DNA was extracted using the Qiagen AllPrep DNA/RNA Mini Kit  and genotyped for https://genome.ucsc.edu/ENCODE/] to investigate the epigenetic landscape of rs6600247 upstream of the RUNX3 promoter, which is strongly associated with AS (p = 4.2 × 10–15) (We used the UCSC genome browser build hg19 and the Roadmap database  was used to quench cross-linking and cells were lysed in cold lysis buffer on ice using a Dounce homogenizer . Cells were resuspended in specific restriction enzyme buffer (10 μL were kept as undigested control). The remaining samples were digested overnight at 37°C with 500 units of Sac1 . Digestion was stopped by the addition of 10% sodium dodecyl sulfate incubated at 65°C for 30 min. T4 ligase  was used to perform ligation for 4 h at 16°C. Proteinase K was added prior to reversal of cross-linking at 65°C overnight. Proteinase K was added to the undigested and digested controls saved earlier. DNA was purified using phenol-chloroform extraction, followed by ethanol precipitation. 3C template was resuspended in 500 ul H2O, while undigested and digested controls in 50 ul. The quality of the chromatin samples was assessed on agarose gels. Bacterial Artificial Chromosome (BAC) preparations were performed similarly as genomic controls. 3C PCR primers were designed along the same strand and same orientation to accomplish specific amplification across 3C ligation junctions. Full list of primers is available in RUNX3 is shown in Chromosome conformation capture (3C) was performed as previously described . BrieflyRUNX3 distal promoter, including few AS-associated SNPs in U937 (monocyte-like) and Jurkat (T-lymphocyte-like) cell lines. The bait was placed at the distal promoter (P2) with amplification primers at the AS-associated SNPs rs6600247 and rs4648889 along with three intergenic regions.We interrogated a genomic region upstream the + and CD14+ cells was isolated with TRIzol  and reverse transcribed with Superscript III  to synthesise cDNA as previously described (RUNX3 sense (s): 5′-ACTCAG CAC CAC AAG CCA CT-3′; RUNX3 antisense (as): 5′-GTC GGA GAA TGG GTT CAG TT-3′. Quantitative PCR was performed in triplicate and the 2−ΔCt method was used to calculate the expression of RUNX3 relative to β-actin .Total RNA from CD8escribed . The speRUNX3 transcription in AS cases and controls was evaluated from previously published data derived from RNA-seq in PBMCs from 72 AS cases and 62 healthy controls and stratified for rs6600247  (http://www.factorbook.org/human/chipseq/tf/)  , and a pseq/tf/) . Taken tonocytes . For thirs6600247 and found that the SNP lies within a c-MYC consensus binding motif (n = 3). We then incubated the same probes with NE from U937 (monocyte-like cells) and observed a major protein/DNA complex binding to the protective T allele, but none with the C allele (n = 3). In both cases, successful competition with a 100-fold excess of unlabelled probe confirmed the specificity of the complex . We also repeated these experiments using CD8+ T-cells and Jurkat NE, showing no differential binding between the two alleles  . We also analysed historical RNA-seq data  . There wseq data  obtainedpression .RUNX3 region, rs6600247, affects the binding of c-MYC to the region of DNA 13 kb upstream of the RUNX3 promoter, which lies in a region of open chromatin in CD14+ monocytes. Further, this region showed enrichment for H3K4Me1 modification in the absence of H3K4me3 or H3K27ac enrichment, suggesting a weak or poised enhancer  block upstream the promoter of RUNX3, there are 22 RUNX3 SNPs that are strongly associated with AS (p ≤ 10–14) (rs6600247 (p = 1.3 × 10–14), is in complete LD with rs4648889 (∼2 kb upstream of the RUNX3 promoter). Conditional analysis established the primacy of the rs4648889 association with AS at RUNX3  . The SNPat RUNX3 , while nat RUNX3  represenRUNX3 promoter has potentially important cell-type-specific functional effects. We show that the rs6600247 AS-risk allele affects c-MYC binding in monocytes, suggesting that c-MYC/RUNX3 modulated pathways could have a role in the pathophysiology of AS. Nevertheless, the region encompassing rs6600247 has no significant physical interaction with the distal RUNX3 promoter, thereby confirming that rs4648889 appears to be the cardinal genetic variant associated with AS at the RUNX3 locus.Clearly the presence of an enhancer-promoter loop alone does not ensure activation of a target gene but it provides a platform where transcription factors can bind and regulate gene/s . Here, w+ T-cell lines exploring psoriasis and psoriatic arthritis disease-associated SNPs and similar methods could be explored in AS  expression and downstream cellular signaling.Further studies are required to identify additional higher order chromatin interactions at this locus. For example, HiChIP has been used to delineate promoter-enhancer interactions in keratinocytes and CD8ed in AS . It is aed in AS . While wof cases . In the RUNX3 and the role that AS-associated SNPs may play in this process. We highlight the importance of functional studies in determining which disease associated SNPs are primarily involved in the pathogenesis of such diseases and the importance of interrogating their role in the appropriate cellular context.In conclusion, this work provides new insights into the complex transcriptional regulation of


Yamaguchi describes recent findings about one of the best-characterized plant transcription factors, LEAFY (LFY), in Arabidopsis. Although many researchers have examined LFY function over the past 30 years, two independent research groups recently revealed that LFY functions as a pioneer transcription factor, one of the master regulators located at the top of the gene regulatory hierarchy. Pioneer transcription factors reprogram the closed chromatin of their target genes and thus play critical roles in specifying when and where downstream targets are expressed to ensure proper cell fate and differentiation. LFY directly binds condensed chromatin, displaces the linker histone H1 in the nucleosome, interacts with chromatin remodeling factors, and opens up chromatin to enable the binding of other factors to specify floral fate  serve as “writers” by depositing methylation marks . The H3K27me3 demethylases identified to date include EARLY FLOWERING 6 (ELF6)/JMJ11, RELATIVE OF ELF6 (REF6)/JMJ12, JMJ13, JMJ30, and JMJ32. These proteins often function in a redundant manner to regulate plant development and environmental responses. Keyzor et al., studied the relationship between ELF6 and JMJ13 and revealed their antagonistic functions during Arabidopsis flower development. Compared to the wild type, elf6 displays increased self-fertility, whereas jmj13 mutants show decreased self-fertility. Based on transcription data, ELF6 promotes carpel elongation by activating expansin genes. JMJ13 represses carpel growth by activating jasmonic acid signal transduction and promotes stamen growth by activating SAUR26 expression.Epigenetic regulation involves multiple mechanisms, including histone modifications. Ornelas-Ayala et al., introduce multiple interacting partners of ULTRAPETALA1 (ULT1) in Arabidopsis. ULT1 controls histone H3 lysine 4 (H3K4me3) levels and counteracts the activity of H3K27me3 “writers.” ULT1 physically interacts with the H3K4me3 writer ATX1 to induce H3K4me3 deposition, and it interacts with tissue-specific transcription factors. ULT and the GARP family transcription factor KANADI1 (KAN1) form a complex that controls gynoecium axis development. ULT and the MYB domain-containing transcription factor ULTRAPETALA INTERACTING FACTOR 1 (UIF1) control floral meristem determinacy by repressing the expression of the stem cell fate gene WUSCHEL. Chromatin structure is altered by chromatin remodelers, such as ATP-dependent chromatin remodeling SWITCH/SUCROSE NON-FERMENTING (SWI/SNF) complexes. The SWI/SNF complex component SWI3B was initially identified as a flowering time regulator  to determine adaxial-abaxial cell fate in leaves.Each epigenetic factor can play multiple roles in controlling gene expression in a tissue-specific manner. Jiang and Zheng summarize the current understanding of the relationship between SPOROCYTELESS/NOZZLE (the core transcription factor required for megaspore mother cell development) and epigenetic regulation at multiple layers. Hirai et al., explored factors downstream of histone deacetylase activity during xylem vessel cell differentiation and identified OVATE FAMILY PROTEIN1 (OFP1), OFP4, and MYB75 as downstream targets. These genes encode transcription factors that form a complex with BEL1-LIKE HOMEODOMAIN6 to control gene expression for cell differentiation.In addition to our knowledge of interacting partners, the factors that function upstream and downstream of each epigenetic factor are not fully understood. Arabidopsis due to the relative ease in performing epigenetic analysis in this plant, a few researchers have performed epigenetic studies in other plant species. Zhang et al., obtained genome-wide H3K27me3 and H3K4me3 profiles in allotetraploid cotton (Gossypium hirsutum). In general, H3K4me3 and H3K27me3 are located around the transcription start sites of active genes and the gene bodies of silenced genes, respectively. Consistent with this notion, the presence of H3K4me3 and H3K27me3 leads to the activation and repression of gene expression, respectively, in allotetraploid cotton. Examining the roles of histone-modifying enzymes in other plant species remains an exciting area for future research.Although the majority of reviews and research articles in this Research Topic describe work in Ouyang et al., developed an alternative method for ChIP-seq called nucleus CUT&Tag (nCUT&Tag). nCUT&Tag can be completed within a day using only 0.01 g of plant tissue as the starting material. Cao et al., explored DNA methylation dynamics using a tissue culture system to prepare plant materials at different stages of development. The combination of such sophisticated systems and highly sensitive techniques will allow researchers to further explore the epigenetic regulation of gene expression during plant development in the future.Many studies related to this Research Topic have revealed the importance of epigenetic regulation in cell fate switching or developmental transitions. These processes occur in a limited number of cells during a limited time window. However, techniques such as chromatin immunoprecipitation followed by sequencing (ChIP-seq) require large numbers of cells and take several days to perform. To address these problems, The author confirms being the sole contributor of this work and has approved it for publication.This work was supported by a grant from the Japan Science and Technology Agency PREST(JPMJPR15QA), a JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas (No. 18H04782), a JSPS KAKENHI Grant-in-Aid for Scientific Research B (No. 18H02465), a Grant-in-Aid for challenging Exploratory Research (No. 19K22431), and a grant from the SECOM Science and Technology Foundation to NY.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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