Amelioration of Brain Histone Methylopathies by Balancing a Writer Eraser Duo KMT2A KDM5C
Abstract Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by seven writer and six eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. Opposing activities of writer eraser enzymes highlight activity modulation as a therapeutic strategy. However, interplay among H3K4me enzymes in the brain remains largely unknown. Here, we show functional interactions of a writer eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann Steiner Syndrome (WDSTS) and mental retardation X linked syndromic Claes Jensen type (MRXSCJ) respectively. Despite opposite enzymatic activities, the WDSTS and MRXSCJ mouse models, deficient for either Kmt2a or Kdm5c, shared similar brain transcriptomes, reduced dendritic spines, and increased aggression. Double mutation of Kmt2a and Kdm5c partially corrected altered H3K4me landscapes and transcriptomes from each single mutants, and clearly reversed dendritic morphology deficits and key behavioral traits including aggression. Thus, our study uncovers common yet mutually suppressive aspects of WDSTS and MRXCJ and provides a proof of principle for balancing a single writer eraser pair to ameliorate their associated disorders.