KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity

Nucleic Acids Res. 2019 Sep 26;47(17):9005-9023. doi: 10.1093/nar/gkz607.


CpG islands (CGIs) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin / enzymology
  • Chromatin / metabolism
  • CpG Islands / genetics*
  • DNA Methylation
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • F-Box Proteins / physiology*
  • Gene Expression Regulation
  • HEK293 Cells
  • Histones / metabolism*
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Jumonji Domain-Containing Histone Demethylases / physiology*
  • Lysine / metabolism
  • Mice
  • Models, Genetic
  • Mouse Embryonic Stem Cells / enzymology
  • Mouse Embryonic Stem Cells / metabolism
  • Promoter Regions, Genetic*
  • RNA Polymerase II / metabolism
  • Transcription, Genetic*


  • Chromatin
  • F-Box Proteins
  • Histones
  • FBXL11 protein, mouse
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm2b protein, mouse
  • RNA Polymerase II
  • Lysine