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

MacroH2A histone variants are shown to mark a subset of enhancers in both normal and cancer cells. In mice, macroH2A deficiency is shown to facilitate increased activity of transcription stem cell-associated transcription factors. 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.

Automated summary

MacroH2A histone variants mark a subset of enhancers in normal and cancer cells, termed "macro-Bound Enhancers", which modulate enhancer activity. They are localized at enhancer elements lacking H3K27ac in a cell type-specific manner, maintaining cell identity. In breast cancer, reactivation of macro-bound enhancers is associated with oncogenic programs, while their repressive role is linked to macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Additionally, macroH2A deficiency enhances the activity of transcription factors associated with stem cell activity in normal mammary stem cells.