2. Academic Validation
  3. Stepwise de novo establishment of inactive X chromosome architecture in early development

Stepwise de novo establishment of inactive X chromosome architecture in early development

  • Nat Genet. 2024 Sep 10. doi: 10.1038/s41588-024-01897-2.
Zhenhai Du # 1 2,  Liangjun Hu # 1 2,  Zhuoning Zou # 1 2,  Meishuo Liu # 2 3,  Zihan Li 1 2,  Xukun Lu 1 2,  Clair Harris 4,  Yunlong Xiang 5,  Fengling Chen 1 2,  Guang Yu 1 2,  Kai Xu 1 2,  Feng Kong 1 2,  Qianhua Xu 1 2,  Bo Huang 6,  Ling Liu 1 2,  Qiang Fan 1 2,  Haifeng Wang 7 8,  Sundeep Kalantry 9,  Wei Xie 10 11
Affiliations

Affiliations

  • 1 Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China.
  • 2 Tsinghua-Peking Center for Life Sciences, Beijing, China.
  • 3 Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 5 Department of Cell Biology and Genetics, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China.
  • 6 Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Tsinghua-Peking Center for Life Sciences, Beijing, China. hfwang@mail.tsinghua.edu.cn.
  • 8 Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China. hfwang@mail.tsinghua.edu.cn.
  • 9 Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA. kalantry@umich.edu.
  • 10 Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, New Cornerstone Science Laboratory, School of Life Sciences, Tsinghua University, Beijing, China. xiewei121@tsinghua.edu.cn.
  • 11 Tsinghua-Peking Center for Life Sciences, Beijing, China. xiewei121@tsinghua.edu.cn.
  • # Contributed equally.
PMID: 39256583 DOI: 10.1038/s41588-024-01897-2
Abstract

X chromosome inactivation triggers a dramatic reprogramming of transcription and chromosome architecture. However, how the chromatin organization of inactive X chromosome is established de novo in vivo remains elusive. Here, we identified an Xist-separated megadomain structure (X-megadomains) on the inactive X chromosome in mouse extraembryonic lineages and extraembryonic endoderm (XEN) cell lines, and transiently in the embryonic lineages, before Dxz4-delineated megadomain formation at later stages in a strain-specific manner. X-megadomain boundary coincides with strong enhancer activities and cohesin binding in an Xist regulatory region required for proper Xist activation in early embryos. Xist regulatory region disruption or cohesin degradation impaired X-megadomains in extraembryonic endoderm cells and caused ectopic activation of regulatory elements and genes near Xist, indicating that cohesin loading at regulatory elements promotes X-megadomains and confines local gene activities. These data reveal stepwise X chromosome folding and transcriptional regulation to achieve both essential gene activation and global silencing during the early stages of X chromosome inactivation.

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