WAVE2与REST/NRSF通过维持异染色质结构来调控基因簇的表达

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. We identify WAVE2 as a key regulator of clustered gene expression via heterochromatin organization. Loss of WAVE2 leads to the expression of Pcdhα genes shifting from stochastic to ubiquitous isoforms, concurrent with altered promoter accessibility. REST/NRSF similarly regulates Pcdhα gene expression by organizing heterochromatin, indicating distinct pathways converge on shared chromatin mechanisms. WAVE2 also regulates perinuclear β‐globin expression via H3K9me3 deposition. These data suggest WAVE2 as a molecular link between actin dynamics, chromatin architecture, and clustered gene regulation.