Histone demethylation maintains Prdm14 and Tsix expression and represses xIst in embryonic stem cells

PLoS One. 2015 May 20;10(5):e0125626. doi: 10.1371/journal.pone.0125626. eCollection 2015.

Abstract

Epigenetic reprogramming is exemplified by the remarkable changes observed in cellular differentiation and X-chromosome inactivation (XCI) in mammalian female cells. Histone 3 lysine 27 trimethylation (H3K27me3) is a modification that suppresses gene expression in multiple contexts including embryonic stem cells (ESCs) and decorates the entire inactive X-chromosome. The conversion of female somatic cells to induced pluripotency is accompanied by X-chromosome reactivation (XCR) and H3K27me3 erasure. Here, we show that the H3K27-specific demethylase Utx regulates the expression of the master regulators for XCI and XCR: Prdm14, Tsix, and Xist. Female ESC transcriptome analysis using a small molecule inhibitor for H3K27 demethylases, GSK-J4, identifies novel targets of H3K27 demethylation. Consistent with a recent report that GSK-J4 can inhibit other histone demethylase, we found that elevated H3K4me3 levels are associated with increased gene expression including Xist. Our data suggest multiple regulatory mechanisms for XCI via histone demethylation.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • DNA Methylation / genetics*
  • DNA-Binding Proteins
  • Embryonic Stem Cells / metabolism*
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Histone Demethylases / metabolism
  • Histones / metabolism*
  • Male
  • Mice
  • RNA, Long Noncoding / genetics*
  • RNA-Binding Proteins
  • Transcription Factors / genetics*
  • Transcriptome / genetics

Substances

  • DNA-Binding Proteins
  • Histones
  • Prdm14 protein, mouse
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • Transcription Factors
  • Tsix transcript, mouse
  • XIST non-coding RNA
  • Histone Demethylases