MacroH2A histone variants modulate enhancer activity to repress oncogenic programs and cellular reprogramming

Commun Biol. 2023 Feb 23;6(1):215. doi: 10.1038/s42003-023-04571-1.

Abstract

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.

Publication types

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

MeSH terms

  • Animals
  • Cellular Reprogramming / genetics
  • Chromatin / genetics
  • Enhancer Elements, Genetic
  • Mice
  • Nuclear Proteins* / metabolism
  • Transcription Factors* / genetics

Substances

  • macroH2A histone
  • Nuclear Proteins
  • Transcription Factors
  • Chromatin