Division of Experimental Pathology, Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Center for Individualized Medicine, Epigenomics program, Mayo Clinic, Rochester, MN, USA.
Commun Biol. 2023 Feb 23;6(1):215. doi: 10.1038/s42003-023-04571-1.
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.
研究人员在鉴定活性增强子元件方面做出了巨大努力，这些元件可通过开放染色质和 H3 赖氨酸 27 乙酰化（H3K27ac）进行注释。然而，除了在发育早期观察到的处于静止状态的增强子和推定的沉默子之外，缺乏 H3K27ac 的顺式调控元件的功能意义仍知之甚少。在这里，我们表明组蛋白变体宏 H2A 标记了正常和癌细胞中增强子的一个子集，我们将其称为“宏结合增强子”，可以调节增强子的活性。我们发现宏 H2A 变体定位于以细胞类型特异性方式缺乏 H3K27ac 的增强子元件上，表明宏 H2A 在非活性增强子中起作用以维持细胞身份。接下来，在乳腺癌中，与致癌程序相关的宏结合增强子的重新激活及其抑制作用与宏 H2A2 作为 BRD4 染色质占据的负调节剂的活性相关。最后，通过对源自小鼠的正常乳腺干细胞进行单细胞表观基因组分析，我们表明宏 H2A 的缺乏促进了与干细胞活性相关的转录因子的活性增加。
