Simultaneous epigenetic perturbation and genome imaging reveal distinct roles of H3K9me3 in chromatin architecture and t
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RESEARCH
Open Access
Simultaneous epigenetic perturbation and genome imaging reveal distinct roles of H3K9me3 in chromatin architecture and transcription Ying Feng1†, Yao Wang2,3†, Xiangnan Wang4, Xiaohui He4, Chen Yang5, Ardalan Naseri6, Thoru Pederson7, Jing Zheng5, Shaojie Zhang6, Xiao Xiao8, Wei Xie2,3* and Hanhui Ma4* * Correspondence: xiewei121@ tsinghua.edu.cn; mahh@ shanghaitech.edu.cn † Ying Feng and Yao Wang contributed equally to this work. 2 Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China 4 School of Life Science and Technology, ShanghaiTech University, Beijing, China Full list of author information is available at the end of the article
Abstract Introduction: Despite the long-observed correlation between H3K9me3, chromatin architecture, and transcriptional repression, how H3K9me3 regulates genome higherorder organization and transcriptional activity in living cells remains unclear. Result: Here, we develop EpiGo (Epigenetic perturbation induced Genome organization)-KRAB to introduce H3K9me3 at hundreds of loci spanning megabases on human chromosome 19 and simultaneously track genome organization. EpiGoKRAB is sufficient to induce genomic clustering and de novo heterochromatin-like domain formation, which requires SETDB1, a methyltransferase of H3K9me3. Unexpectedly, EpiGo-KRAB-induced heterochromatin-like domain does not result in widespread gene repression except a small set of genes with concurrent loss of H3K4me3 and H3K27ac. Ectopic H3K9me3 appears to spread in inactive regions but is largely restricted from transcriptional initiation sites in active regions. Finally, Hi-C analysis showed that EpiGo-KRAB reshapes existing compartments mainly at compartment boundaries. Conclusions: These results reveal the role of H3K9me3 in genome organization could be partially separated from its function in gene repression.
Background Human genome is organized in a hierarchy manner from kilobase to megabase scales such as nucleosome, loops, topologically associated domains (TADs), and A/B compartments [1–4]. It has been proposed that the loop extrusion drives TAD formation [5]. On the other hand, liquid-liquid phase separation is suggested to mediate genome compartmentalization [5, 6]. For example, heterochromatin protein HP1α undergoes liquid-liquid demixing suggesting a role of phase separation in heterochromatin domain formation [7–9]. Heterochromatin drives compartmentalization in the inverted nuclei of rods in nocturnal mammals [10]. The co-segregated compartments often share similar © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
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