Bryan Elana, Valsakumar Devisree, Idigo Nwamaka J, Warburton Marie, Webb Kimberly M, McLaughlin Katy A, Spanos Christos, Lenci Simone, Major Viktoria, Ambrosi Christina, Andrews Simon, Baubec Tuncay, Rappsilber Juri, Voigt Philipp
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK; Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
Mol Cell. 2025 Feb 6;85(3):471-489.e12. doi: 10.1016/j.molcel.2024.12.002. Epub 2024 Dec 27.
Promoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one of the two marks. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here, we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, thereby promoting a poised state. Strikingly, the bivalent mark combination further promotes recruitment of specific chromatin proteins that are not recruited by each mark individually, including the lysine acetyltransferase (KAT) complex KAT6B. Knockout of KAT6B blocks neuronal differentiation, demonstrating that KAT6B is critical for proper bivalent gene expression during ESC differentiation. These findings reveal how readout of the bivalent histone marks directly promotes a poised state at developmental genes while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.
胚胎干细胞（ESC）中发育基因的启动子以不对称核小体构象中的组蛋白H3赖氨酸4三甲基化（H3K4me3）和H3K27me3为特征，每个姐妹组蛋白H3仅携带这两种标记中的一种。这些双价结构域被认为使基因在分化时能够及时激活。在这里，我们表明不对称双价核小体招募抑制性H3K27me3结合蛋白，但未能富集激活H3K4me3结合蛋白，从而促进一种准备就绪的状态。引人注目的是，双价标记组合进一步促进了特定染色质蛋白的招募，而这些蛋白不会被每个标记单独招募，包括赖氨酸乙酰转移酶（KAT）复合物KAT6B。敲除KAT6B会阻断神经元分化，表明KAT6B对于ESC分化过程中双价基因的正确表达至关重要。这些发现揭示了双价组蛋白标记的读出如何直接促进发育基因的准备就绪状态，同时突出了核小体不对称性对于组蛋白标记读出和功能的关键作用。
