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

Wazim Mohammed Ismail, Amelia Mazzone, Flavia G. Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S. Bagwell, Stephanie L. Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A. Leach, Luis F. Duarte, Chandandeep S. Nagi, Saul Carcamo, Chi Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong Heon LeeFergus J. Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number215
JournalCommunications Biology
Issue number1
StatePublished - Dec 2023

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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