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CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation

Abstract

Chromatin is spatially organized into three-dimensional structures at different levels including A/B compartments, topologically associating domains and loops. The canonical CTCF-mediated loop extrusion model can explain the formation of loops. However, the organization mechanisms underlying long-range chromatin interactions such as interactions between A–A compartments are still poorly understood. Here we show that different from the canonical loop extrusion model, RYBP-mediated phase separation of CTCF organizes inter-A compartment interactions. Based on this model, we designed and verified an induced CTCF phase separation system in embryonic stem cells (ESCs), which facilitated inter-A compartment interactions, improved self-renewal of ESCs and inhibited their differentiation toward neural progenitor cells. These findings support a novel and non-canonical role of CTCF in organizing long-range chromatin interactions via phase separation.

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Fig. 1: CTCF organizes inter-A compartment interactions.
Fig. 2: CTCF exhibits phase separation behavior in the nucleus.
Fig. 3: RYBP facilitates CTCF to undergo phase separation.
Fig. 4: RYBP depletion attenuates CTCF-mediated inter-A compartment interactions.
Fig. 5: Induced CTCF phase separation restores inter-A compartment interactions impaired by RYBP depletion.
Fig. 6: Induced CTCF phase separation improves self-renewal of ESCs.
Fig. 7: Induced CTCF phase separation inhibits ESC differentiation toward NPCs.

Data availability

Regarding results generated from public sequencing data, data information has been provided in figure legends. In addition to the emphasized public data, other sequencing data generated in this study have been deposited at NCBI GEO under accession number GSE147919. All the accession numbers of sequencing data are summarized in Supplementary information, Table S7. All of the software used in this study are listed in Supplementary information, Table S8.

Code availability

Regarding results generated from public sequencing data, data information has been provided in figure legends. In addition to the emphasized public data, other sequencing data generated in this study have been deposited at NCBI GEO under accession number GSE147919. All the accession numbers of sequencing data are summarized in Supplementary information, Table S7. All of the software used in this study are listed in Supplementary information, Table S8.

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Acknowledgements

This research was funded by grants from the National Key R&D Program (2017YFA0102800), the National Natural Science Foundation of China (31970811, 31771639 and 32170798), the Guangdong Regenerative Medicine and Health of Guangdong Laboratory Frontier Exploration Project (2018GZR110105007), the Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S029), Guangdong Basic and Applied Basic Research Foundation (2021B1515120063) to J.D.; the National Natural Science Foundation of China (32100497) and Post-doctoral Program (2021M703760) to C.W.; the Fundamental Research Funds for the Central Universities of Jinan University (Natural Science) (116210004) and China Postdoctoral Science Foundation (55350600), the Natural Science Foundation of Guangdong Province, China (2021A1515010938) to J.S.; the National Natural Science Foundation of China (31900519) to F.L.; the Natural Science Foundation of China (32025006, 31871266) and National Key R&D Program of China (2021YFA1100300, 2016YFA0100103) to L.J. and C.L. Part of the data analysis was performed on the High Performance Computing Platform of the Center for Life Sciences, Peking University. This work was also supported in part by the State Key R&D Program of China (2017YFA0505503), the National Natural Science Foundation of China (81890991), CAS Interdisciplinary Innovation Team (JCTD-2020-04), Beijing Municipal Natural Science Foundation (Z200021) to J.G. For FISH experiment, we thank the help from Morningstar Genes Intelligence Ltd. (MGI Beijing), China, and the effort from Ms. Rui Wang and Ms. Yuyao Song in School of Life Sciences, and in Class of Basic Sciences, Tsinghua Xuetang talent program, Tsinghua University, China. We thank Hongjie Yao for the gift of shRNA targeting Rybp, and thank Guohong Li for the gift of RING1B-AID cell line. We also thank Yuanjun Guan for image data analysis and Yali Tang for FACS analysis.

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C.W., L.J., X.H. and J.T. conceived the experiments. C.W., L.J., X.H., J.T., M.W., S.J., Y.H., J.N., L.Q., and L.M. performed the experiments. L.J., P.Z., J.S., X.L., T.L. and C.W. performed the data analysis and statistical calculations. Y.S., and J.G. supervised the design of the FISH probe. C.W., L.J., X.H., J.T., J.W., F.L., L.F., X.T. and J.L. prepared the manuscript. J.D. and C.L. supervised the project.

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Correspondence to Cheng Li or Junjun Ding.

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Wei, C., Jia, L., Huang, X. et al. CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation. Cell Res 32, 744–760 (2022). https://doi.org/10.1038/s41422-022-00676-0

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