PDF(Pubmed)
Abstract：
Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural stem cells (NSC). PHF2 loss impairs DNA replication due to the activation of dormant replication origins in NSC. Notably, the PHF2/RAD21 co-bound genomic regions are characterized by CTCF enrichment and epigenomic features that resemble efficient, active replication origins, and can act as boundaries to separate adjacent domains. Accordingly, PHF2 loss weakens TADs and chromatin loops at the co-bound loci due to reduced RAD21 occupancy. The observed topological and DNA replication defects in PHF2 KO NSC support a cohesin-dependent mechanism. Furthermore, we demonstrate that the PHF2/RAD21 complex exerts little effect on gene regulation, and that PHF2\'s histone-demethylase activity is dispensable for normal DNA replication and proliferation of NSC. We propose that PHF2 may serve as a topological accessory to cohesin for cohesin localization to TADs and chromatin loops, where cohesin represses dormant replication origins directly or indirectly, to sustain DNA replication in NSC.
摘要：
Cohesin在拓扑关联域（TAD）的组织中起着至关重要的作用，影响基因表达和DNA复制时间。表观遗传调节因子是否可以通过粘附素介导DNA复制来影响TAD仍然难以捉摸。这里,我们发现组蛋白去甲基酶PHF2与RAD21相关，RAD21是粘附素的核心亚基，调节小鼠神经干细胞（NSC）中的DNA复制。由于NSC中休眠复制起点的激活,PHF2损失损害DNA复制。值得注意的是,PHF2/RAD21共结合基因组区域的特征是CTCF富集和表观基因组特征，活跃的复制起点，并且可以充当分隔相邻域的边界。因此，由于RAD21占用率降低，PHF2丢失会削弱共结合基因座处的TAD和染色质环。在PHF2KONSC中观察到的拓扑和DNA复制缺陷支持依赖粘附素的机制。此外，我们证明了PHF2/RAD21复合物对基因调控几乎没有影响，PHF2的组蛋白脱甲基酶活性对于正常的DNA复制和NSC的增殖是不必要的。我们建议PHF2可以作为粘附素的拓扑附件，用于粘附素定位到TAD和染色质环，其中cohesin直接或间接抑制休眠复制起点，来维持NSC中的DNA复制。
