Dzip3 regulates developmental genes in mouse embryonic stem cells by reorganizing 3D chromatin conformation [RNA-seq]

In mouse embryonic stem cells (mES cells), ubiquitylation of histone H2A lysine 119 represses a large number of developmental genes and maintains mES cell pluripotency. It has been suggested that a number of H2A ubiquitin ligases as well as deubiquitylases and related peptide fragments contribute to a delicate balance between self-renewal and multi-lineage differentiation in mES cells. Here, we tested whether known H2A ubiquitin ligases and deubiquitylases are involved in mES cell regulation and discovered that Dzip3, the E3 ligase of H2AK119, represses differentiation-inducible genes as well as Ring1B. The two sets of target genes partially overlapped but had different spectra. We found that Dzip3 represses gene expression by orchestrating changes in 3D organization in addition to regulating ubiquitylation of H2A. Our results shed light on the epigenetic mechanism of transcriptional regulation, which depends on 3D chromatin reorganization to regulate mES cell differentiation.

在小鼠胚胎干细胞（mES细胞）中，组蛋白H2A赖氨酸119位点的泛素化可抑制大量发育基因的表达，并维持mES细胞的多能性。已有研究表明，多种H2A泛素连接酶、去泛素化酶及相关肽段共同参与维持mES细胞自我更新与多谱系分化之间的精细平衡。本研究针对已报道的H2A泛素连接酶与去泛素化酶是否参与mES细胞调控展开验证，结果发现H2AK119的E3连接酶Dzip3与Ring1B均可抑制分化诱导基因的表达。二者的靶基因集合存在部分重叠，但靶基因谱各具差异。研究发现，Dzip3除调控H2A的泛素化修饰外，还通过重塑三维染色质结构来抑制基因表达。本研究结果揭示了依赖三维染色质重塑以调控mES细胞分化的转录调控表观遗传机制。