Genomic Profiling by ALaP-Seq Reveals Transcriptional Regulation by PML Bodies through DNMT3A Exclusion
Genomic Profiling by ALaP-Seq Reveals Transcriptional Regulation by PML Bodies through DNMT3A Exclusion
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DOI：
10.1016/j.molcel.2020.04.004
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发表时间：
2020-05-07
期刊：
影响因子：
16
通讯作者：
Miyanari, Yusuke
中科院分区：
文献类型：
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作者：
Kurihara, Misuzu;Kato, Kagayaki;Miyanari, Yusuke
早幼粒细胞白血病（PML）体是一个与染色质物理相关的相分离的核结构，这意味着它在基因组功能中起着至关重要的作用。然而，其在转录调控中的作用在很大程度上是未知的。我们开发了APEX介导的染色质标记和纯化（阿拉普）来鉴定PML小体附近的基因组区域。我们发现，PML小体与整个基因组的活性调控区相关，并与小鼠胚胎干细胞中Y染色体短臂（YS 300）的300 kb相似。PML体与YS 300的关联对于相邻Y连锁簇基因的转录活性是必需的。从机制上讲，PML小体提供了从头DNA甲基转移酶DNMT 3A无法进入的特定核空间，导致Y-连锁基因启动子稳定维持低甲基化状态。我们的研究强调了3D核空间中基因调控的新机制，并为基因组功能的核结构的功能特性提供了见解。
The promyelocytic leukemia (PML) body is a phase-separated nuclear structure physically associated with chromatin, implying its crucial roles in genome functions. However, its role in transcriptional regulation is largely unknown. We developed APEX-mediated chromatin iabeling and purification (ALaP) to identify the genomic regions proximal to PML bodies. We found that PML bodies associate with active regulatory regions across the genome and with similar to 300 kb of the short arm of the Y chromosome (YS300) in mouse embryonic stem cells. The PML body association with YS300 is essential for the transcriptional activity of the neighboring Y-linked clustered genes. Mechanistically, PML bodies provide specific nuclear spaces that the de novo DNA methyltransferase DNMT3A cannot access, resulting in the steady maintenance of a hypo-methylated state at Y-linked gene promoters. Our study underscores a new mechanism for gene regulation in the 3D nuclear space and provides insights into the functional properties of nuclear structures for genome function.