Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation

Nat Commun. 2021 Jun 9;12(1):3499. doi: 10.1038/s41467-021-23610-1.

Abstract

A hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments, and into topologically associating domains (TADs). Both structures were regarded to be absent from the inactive mouse X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC reprogramming system and high-resolution Hi-C to produce a time course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we observe A/B-like compartments on the inactive X harbouring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, concomitant with downregulation of Xist. Importantly, we find that TAD formation precedes transcription and initiates from Xist-poor compartments. Here, we show that TAD formation and transcriptional reactivation are causally independent during X-reactivation while establishing Xist as a common denominator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Reprogramming / genetics
  • Chromatin Assembly and Disassembly
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Mice
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Sex Chromatin / genetics
  • Sex Chromatin / metabolism
  • Transcription, Genetic*
  • X Chromosome / genetics
  • X Chromosome / metabolism*
  • X Chromosome Inactivation / genetics*

Substances

  • RNA, Long Noncoding
  • XIST non-coding RNA