Our **data** demonstrates phosphorylation network and transcriptional regulatory network utilize different network motifs. The motif ''regulator chain'' is only enriched in phosphorylation network. Based on the linear regulatory model ( Figure 1C), it can be inferred that KPFN is more predictive of co-function than KBN, which coincides with our observation. The ''bi-input'' motif is also enriched in phosphorylation network, resulting in a genetic buffering effect of phosphorylation events [4]. In transcriptional regulatory networks ''feed forward loop'' (FFL) motif was enriched, which have already been widely discussed [2] [15] [16]. The motifs with loop structure within regulators (bicomponent loop1, bi-component loop2) are also enriched in transcriptional regulatory networks. In these motifs, two TFs transcribe each other, and generate a bi-stable system, which switches between two alternative states [17] [2]. The two motifs tend to characterize an important mode in transcriptional regulation. TFs cooperate to regulate a set of genes (bi-component loop 2), but their functions are not completely redundant (bicomponent loop 1). For example, Ste12 and Tec1 are two TFs that co-regulate genes in filamentous pathway (for example, Kss1), but only Ste12 activates genes in mating pheromone pathway (for example, Ste3) ( Figure 2). In this case, the resultant signatures are divergent but their binding profiles overlap with each other on the co-regulated genes ( Figure S1). This phenomenon is termed mixed epistasis in phosphorylation network [4], where two kinase partly buffer each other, and also have unique functions themselves. We demonstrate that this definition can also be extended to transcriptional network according to the enriched bi-component loops. Because of the enriched buffering relationships in transcriptional regulatory networks, TFBN is more predictive of co-function than TFFN, which is also consistent with our observation. In the combined network, the enriched motif is FFL, which couples phosphorylation with transcription. A previous study showed that FFL formed by kinase CDK1 and transcriptional factors was important to drive temporal transcriptional responses in cell cycle regulation [11].