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Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-02-24 , DOI: 10.1038/s41588-020-0581-x
Chew Yee Ngan 1 , Chee Hong Wong 1 , Harianto Tjong 1 , Wenbo Wang 2, 3 , Rachel L Goldfeder 1 , Cindy Choi 4 , Hao He 1 , Liang Gong 1 , Junyan Lin 4 , Barbara Urban 2 , Julianna Chow 4 , Meihong Li 1 , Joanne Lim 4 , Vivek Philip 2 , Stephen A Murray 2 , Haoyi Wang 5 , Chia-Lin Wei 1
Affiliation  

Lineage-specific gene expression is modulated by a balance between transcriptional activation and repression during animal development. Knowledge about enhancer-centered transcriptional activation has advanced considerably, but silencers and their roles in normal development remain poorly understood. Here, we performed chromatin interaction analyses of Polycomb repressive complex 2 (PRC2), a key inducer of transcriptional gene silencing, to uncover silencers, their molecular identity and associated chromatin connectivity. Systematic analysis of cis-regulatory silencer elements reveals their chromatin features and gene-targeting specificity. Deletion of certain PRC2-bound silencers in mice results in transcriptional derepression of their interacting genes and pleiotropic developmental phenotypes, including embryonic lethality. While some PRC2-bound elements function as silencers in pluripotent cells, they can transition into active tissue-specific enhancers during development, highlighting their regulatory versatility. Our study characterizes the molecular profile of silencers and their associated chromatin architectures, and suggests the possibility of targeted reactivation of epigenetically silenced genes.

中文翻译:

染色质相互作用分析阐明了 PRC2 结合消音器在小鼠发育中的作用。

谱系特异性基因表达受动物发育过程中转录激活和抑制之间的平衡调节。关于以增强子为中心的转录激活的知识已经有了长足的进步,但消音器及其在正常发育中的作用仍然知之甚少。在这里,我们对转录基因沉默的关键诱导剂 Polycomb 抑制复合物 2 (PRC2) 进行了染色质相互作用分析,以揭示沉默子、它们的分子身份和相关的染色质连接性。对顺式调节消音元件的系统分析揭示了它们的染色质特征和基因靶向特异性。在小鼠中删除某些与 PRC2 结合的消音器会导致其相互作用基因和多效性发育表型的转录抑制,包括胚胎致死率。虽然一些与 PRC2 结合的元素在多能细胞中起到消音器的作用,但它们可以在发育过程中转变为活跃的组织特异性增强剂,突出了它们的调节多功能性。我们的研究描述了消音器的分子谱及其相关的染色质结构,并提出了对表观遗传沉默基因进行靶向再激活的可能性。
更新日期:2020-02-24
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