XIST directly regulates X-linked and autosomal genes in naive human pluripotent cells

Iris Dror; Tsotne Chitiashvili; Shawn Y X Tan; Clara T Cano; Anna Sahakyan; Yolanda Markaki; Constantinos Chronis; Amanda J Collier; Weixian Deng; Guohao Liang; Yu Sun; Anna Afasizheva; Jarrett Miller; Wen Xiao; Douglas L Black; Fangyuan Ding; Kathrin Plath

doi:10.1016/j.cell.2023.11.033

XIST directly regulates X-linked and autosomal genes in naive human pluripotent cells

Cell. 2024 Jan 4;187(1):110-129.e31. doi: 10.1016/j.cell.2023.11.033.

Authors

Iris Dror¹, Tsotne Chitiashvili¹, Shawn Y X Tan¹, Clara T Cano¹, Anna Sahakyan¹, Yolanda Markaki², Constantinos Chronis³, Amanda J Collier¹, Weixian Deng¹, Guohao Liang⁴, Yu Sun¹, Anna Afasizheva¹, Jarrett Miller¹, Wen Xiao⁵, Douglas L Black⁵, Fangyuan Ding⁶, Kathrin Plath⁷

Affiliations

¹ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute for Structural and Chemical Biology & Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
³ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.
⁴ Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA.
⁵ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USA; Department of Developmental and Cell Biology, Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA.
⁷ Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: kplath@mednet.ucla.edu.

PMID: 38181737
PMCID: PMC10783549 (available on 2025-01-04)
DOI: 10.1016/j.cell.2023.11.033

Abstract

X chromosome inactivation (XCI) serves as a paradigm for RNA-mediated regulation of gene expression, wherein the long non-coding RNA XIST spreads across the X chromosome in cis to mediate gene silencing chromosome-wide. In female naive human pluripotent stem cells (hPSCs), XIST is in a dispersed configuration, and XCI does not occur, raising questions about XIST's function. We found that XIST spreads across the X chromosome and induces dampening of X-linked gene expression in naive hPSCs. Surprisingly, XIST also targets specific autosomal regions, where it induces repressive chromatin changes and gene expression dampening. Thereby, XIST equalizes X-linked gene dosage between male and female cells while inducing differences in autosomes. The dispersed Xist configuration and autosomal localization also occur transiently during XCI initiation in mouse PSCs. Together, our study identifies XIST as the regulator of X chromosome dampening, uncovers an evolutionarily conserved trans-acting role of XIST/Xist, and reveals a correlation between XIST/Xist dispersal and autosomal targeting.

Keywords: X chromosome dampening; X chromosome inactivation; XIST; dispersed localization; dosage compensation; human pluripotent stem cells; lncRNA; polycomb-repressive complexes; sexual dimorphism; trans-acting.

Publication types

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

MeSH terms

Animals
Female
Gene Silencing
Genes, X-Linked*
Humans
Male
Mice
Pluripotent Stem Cells / metabolism
RNA, Long Noncoding* / genetics
X Chromosome* / genetics

Substances

RNA, Long Noncoding

Abstract

Publication types

MeSH terms

Substances

Grants and funding