Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

Feng Wang; Kurtis N McCannell; Ana Bošković; Xiaochun Zhu; JongDae Shin; Jun Yu; Judith Gallant; Meg Byron; Jeanne B Lawrence; Lihua J Zhu; Stephen N Jones; Oliver J Rando; Thomas G Fazzio; Ingolf Bach

doi:10.1016/j.celrep.2017.12.004

Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

Cell Rep. 2017 Dec 26;21(13):3691-3699. doi: 10.1016/j.celrep.2017.12.004.

Authors

Affiliations

¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
² Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁴ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁵ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁶ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: ingolf.bach@umassmed.edu.

Abstract

During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI depend on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI. Here, we demonstrate the existence of Rlim-dependent and Rlim-independent pathways for rXCI in differentiating female ESCs. Upon uncoupling these pathways, we find more efficient Rlim-independent XCI in ESCs cultured under physiological oxygen conditions. Our results revise current models of rXCI and suggest that caution must be taken when comparing XCI studies in ESCs and mice.

Keywords: EB differentiation; ESC; Rlim; Rlim-independent XCI; Rnf12; X chromosome inactivation; XCI; XCI regulation; Xist; physiological oxygen levels.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Culture Techniques
Female
Mice
Mouse Embryonic Stem Cells / metabolism*
Mutant Proteins / metabolism
Ubiquitin-Protein Ligases / metabolism*
X Chromosome Inactivation / genetics*

Substances

Mutant Proteins
Rlim protein, mouse
Ubiquitin-Protein Ligases

Abstract

Publication types

MeSH terms

Substances

Grants and funding