WAVE2 and REST / NRSF Regulate Clustered Gene Expression by Maintaining Heterochromatin Organization

ABSTRACT

The actin polymerization machinery, comprising the ARP2/3 complex and its activators, the WASP family proteins, has been implicated in regulating a broad spectrum of nuclear processes, such as transcriptional regulation and nuclear organization. Here, using clustered protocadherin ( cPcdh ) and β‐globin genes as model systems, we showed that WAVE2 , a member of the WASP family, regulates chromatin organization by maintaining heterochromatin dynamics. Specifically, by CRISPR DNA‐fragment editing, in conjunction with integrated analyses of ChIP‐seq, MeDIP‐seq, ATAC‐seq, QHR‐4C, and RNA‐seq, we showed that deposition of H3K9me3, a key heterochromatin mark, is significantly decreased at the cPcdh locus upon WAVE2 deletion, concurrent with aberrant accumulation of CTCF/cohesin complex at promoter regions and spatial reorganization of chromatin architecture around the nucleolus. In addition, REST/NRSF exerts a similar heterochromatin‐dependent effect on the cPcdh locus. Finally, genetic and genomic data showed that WAVE2 regulates β‐globin gene expression by maintaining heterochromatin status. Together, our data suggested that WAVE2 and REST/NRSF regulate developmental expression of clustered genes in a heterochromatin‐dependent manner.