European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences, Heidelberg, Germany.
Nat Commun. 2024 Aug 30;15(1):7557. doi: 10.1038/s41467-024-51785-w.
Histone modifications are associated with distinct transcriptional states, but it is unclear whether they instruct gene expression. To investigate this, we mutate histone H3.3 K9 and K27 residues in mouse embryonic stem cells (mESCs). Here, we find that H3.3K9 is essential for controlling specific distal intergenic regions and for proper H3K27me3 deposition at promoters. The H3.3K9A mutation resulted in decreased H3K9me3 at regions encompassing endogenous retroviruses and induced a gain of H3K27ac and nascent transcription. These changes in the chromatin environment unleash cryptic enhancers, resulting in the activation of distinctive transcriptional programs and culminating in protein expression normally restricted to specialized immune cell types. The H3.3K27A mutant disrupts the deposition and spreading of the repressive H3K27me3 mark, particularly impacting bivalent genes with higher basal levels of H3.3 at promoters. Therefore, H3.3K9 and K27 crucially orchestrate repressive chromatin states at cis-regulatory elements and bivalent promoters, respectively, and instruct proper transcription in mESCs.
组蛋白修饰与独特的转录状态相关，但它们是否指导基因表达尚不清楚。为了研究这个问题，我们在小鼠胚胎干细胞（mESCs）中突变组蛋白 H3.3 的 K9 和 K27 残基。在这里，我们发现 H3.3K9 对于控制特定的远端基因间区域和在启动子处正确沉积 H3K27me3 至关重要。H3.3K9A 突变导致包含内源性逆转录病毒的区域中的 H3K9me3 减少，并诱导 H3K27ac 和新生转录的增加。染色质环境的这些变化释放出隐蔽的增强子，导致独特的转录程序的激活，并最终导致通常局限于专门免疫细胞类型的蛋白质表达。H3.3K27A 突变破坏了抑制性 H3K27me3 标记的沉积和扩散，特别是对具有更高启动子处 H3.3 基础水平的双价基因产生影响。因此，H3.3K9 和 K27 分别在顺式调控元件和双价启动子处精心协调抑制性染色质状态，并在 mESCs 中指导适当的转录。
