Volume 31, No 6, Jun 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 6, June 2021: 613-630   |  Open Access

ORIGINAL ARTICLES

Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome

J. Yuyang Lu¹ , Lei Chang^2,3 , Tong Li¹ , Ting Wang¹ , Yafei Yin¹ , Ge Zhan¹ , Xue Han¹ , Ke Zhang¹ , Yibing Tao¹ , Michelle Percharde^4,5 , Liang Wang¹ , Qi Peng¹ , Pixi Yan¹ , Hui Zhang¹ , Xianju Bi¹ , Wen Shao¹ , Yantao Hong¹ , Zhongyang Wu¹ , Runze Ma⁶ , Peizhe Wang¹ , Wenzhi Li¹ , Jing Zhang¹ , Zai Chang¹ , Yingping Hou² , Bing Zhu⁶ , Miguel Ramalho-Santos⁷ , Pilong Li¹ , Wei Xie¹ , Jie Na¹ , Yujie Sun^2,* , Xiaohua Shen^1,*

¹Tsinghua-Peking Joint Center for Life Sciences, School of Medicine and School of Life Sciences, Tsinghua University, Beijing 100084, China
²State Key Laboratory of Membrane Biology, Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, and College of Future Technology, Peking University, Beijing 100871, China
³Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, Guangdong 510005, China
⁴MRC London Institute of Medical Sciences (LMS), London W120NN, UK
⁵Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London W120NN, UK
⁶National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
⁷Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario M5T 3H7, Canada
These authors contributed equally: Ting Wang, Yafei Yin, Ge Zhan, Xue Han, Ke Zhang, Yibing Tao These authors contributed equally as co-first authors: J. Yuyang Lu, Lei Chang, Tong Li Correspondence: Yujie Sun(sun_yujie@pku.edu.cn)Xiaohua Shen(xshen@tsinghua.edu.cn)

Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation. In an effort to unravel the basic principle underlying genome folding, here we focus on the genome itself and report a fundamental role for L1 (LINE1 or LINE-1) and B1/Alu retrotransposons, the most abundant subclasses of repetitive sequences, in chromatin compartmentalization. We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains, and characterizes and predicts Hi-C compartments. Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle. In addition, de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts. Importantly, depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength, and disrupts the nuclear segregation of L1- or B1-rich chromosomal sequences at genome-wide and individual sites. Mechanistically, nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1α suggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization. Taken together, we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure. Our model explains the robustness of genome folding into a common conserved core, on which dynamic gene regulation is overlaid across cells.

https://doi.org/10.1038/s41422-020-00466-6

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