Stage-specific Epigenetic Gene Priming by the MSL Complex Orchestrates Neurogenesis

Precise regulation of epigenetic marks is critical for proper lineage commitment throughout neurodevelopment. Mutations in members of the MSL acetyltransferase complex (MSLc), specific for H4K16ac, are associated with neurodevelopmental disorders in humans. However, the precise gene targets and enzymatic contributions of the MSLc during neural differentiation remain unclear. Through single-cell multi-omics analysis, we demonstrate that Msl1 deletion leads to severe neurodevelopmental defects, culminating in embryonic lethality by E10.5. Using a rapid depletion system, we uncoupled acute transcriptional effects from epigenetic memory and found that MSLc-mediated gene priming is responsible for faithful upregulation of crucial neurodevelopmental gene programs. The priming of the MSLc target genes is limited to the initial stages of differentiation following neuronal induction, where the MSLc facilitates chromatin accessibility at regulatory regions to, allowing for selective enhancer-promoter interactions and subsequent gene activation. Our study identifies the MSLc as a crucial epigenetic regulator during neurodevelopment, providing molecular insights into MSLc-associated developmental disorders.表观遗传标记（epigenetic marks）的精准调控，对神经发育全程的正常谱系特化至关重要。特异性介导组蛋白H4赖氨酸16乙酰化（H4K16ac）的MSL乙酰转移酶复合物（MSL acetyltransferase complex, MSLc），其亚基突变与人类神经发育障碍密切相关。然而，MSLc在神经分化过程中的确切基因靶点及其酶促功能机制仍有待阐明。本研究通过单细胞多组学分析（single-cell multi-omics analysis）证实，Msl1基因敲除会引发严重的神经发育缺陷，最终导致胚胎在发育至E10.5时致死。借助快速耗竭系统（rapid depletion system），本研究将急性转录效应与表观遗传记忆解耦联后发现，MSLc介导的基因预激活（gene priming）是确保关键神经发育基因程序得以忠实上调的核心机制。MSLc靶基因的预激活仅局限于神经元诱导后的分化初始阶段：在此阶段，MSLc可促进调控区域的染色质可及性，从而介导选择性增强子-启动子相互作用，进而激活后续的基因表达。本研究证实MSLc是神经发育过程中关键的表观遗传调控因子，为解析MSLc相关发育障碍的分子机制提供了重要理论依据。