SWI/SNF complex mediated ZNF410 cooperative binding maintains chromatin accessibility and enhancer activity

Clustering of multiple transcription factor binding sites (TFBSs) for the same TF has proved to be a pervasive feature of cis-regulatory elements in eukaryotic genome. However, contribution of binding sites within the homotypic clusters of TFBSs (HCTs) to TF binding and target gene expression remains to be understood. Here, we characterize the CHD4 enhancers that harbor unique functional ZNF410 HCTs genome-wide. We uncover that ZNF410 controls chromatin accessibility and activity of the CHD4 enhancer regions. We demonstrate that ZNF410 binds to the HCTs in a collaborative fashion, further conferring transcriptional activation. Especially, three ZNF410 motifs (sub-HCTs) located at 3´ end of the distal enhancer act as “switch motifs” to control the chromatin accessibility and enhancer activity. Mechanistically, SWI/SNF complex is selectively required to mediate cooperative ZNF410 binding for CHD4 expression. Together, our findings expose a complex functional hierarchy of homotypic clustered motifs, which cooperates to fine-tune target gene expression.