KDM5B regulates embryonic stem cell self-renewal and represses cryptic intragenic transcription

Liangqi Xie, Carl Pelz, Wensi Wang, Amir Bashar, Olga Varlamova, Sean Shadle, Soren Impey

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Although regulation of histone methylation is believed to contribute to embryonic stem cell (ESC) self-renewal, the mechanisms remain obscure. We show here that the histone H3 trimethyl lysine 4 (H3K4me3) demethylase, KDM5B, is a downstream Nanog target and critical for ESC self-renewal. Although KDM5B is believed to function as a promoter-bound repressor, we find that it paradoxically functions as an activator of a gene network associated with self-renewal. ChIP-Seq reveals that KDM5B is predominantly targeted to intragenic regions and that it is recruited to H3K36me3 via an interaction with the chromodomain protein MRG15. Depletion of KDM5B or MRG15 increases intragenic H3K4me3, increases cryptic intragenic transcription, and inhibits transcriptional elongation of KDM5B target genes. We propose that KDM5B activates self-renewal-associated gene expression by repressing cryptic initiation and maintaining an H3K4me3 gradient important for productive transcriptional elongation.

Original languageEnglish (US)
Pages (from-to)1473-1484
Number of pages12
JournalEMBO Journal
Volume30
Issue number8
DOIs
StatePublished - Apr 20 2011

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Keywords

  • chromatin
  • epigenetics
  • histone demethylase
  • self-renewal
  • transcriptional elongation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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