Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers. In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner. How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown. Using analysis of genome-wide histone modifications, TF binding, chromatin accessibility and gene expression, we show that HNF4A is essential for an active chromatin state. Using HNF4A loss and gain of function experiments in vivo and in cell lines in vitro, we show that HNF4A affects H3K4me1, H3K27ac and chromatin accessibility, highlighting its contribution to the establishment and maintenance of a transcriptionally permissive epigenetic state. Mechanistically, HNF4A interacts with the mixed-lineage leukaemia 4 (MLL4) complex facilitating recruitment to HNF4A-bound regions. Our findings indicate that HNF4A enriches H3K4me1, H3K27ac and establishes chromatin opening at transcriptional regulatory regions.

肝细胞核因子 4A （HNF4A/NR2a1） 是肝细胞身份的转录调节因子，主要通过与增强子结合来控制对肝功能至关重要的基因。在哺乳动物细胞中，活性和引发的增强子以细胞类型特异性方式通过组蛋白 3 （H3） 在赖氨酸 4 （K4） （H3K4me1） 位点的单甲基化来标记。这种修饰是如何在与转录因子 （TFs） 相关的增强子上建立和维持的仍然未知。通过分析全基因组组蛋白修饰、TF 结合、染色质可及性和基因表达，我们表明 HNF4A 对于活性染色质状态至关重要。使用体内和体外细胞系中的 HNF4A 功能丧失和获得实验，我们表明 HNF4A 影响 H3K4me1、H3K27ac 和染色质的可及性，突出了其对建立和维持转录允许的表观遗传状态的贡献。从机制上讲，HNF4A 与混合谱系白血病 4 （MLL4） 复合物相互作用，促进募集到 HNF4A 结合区域。我们的研究结果表明，HNF4A 富集 H3K4me1 、 H3K27ac 并在转录调控区域建立染色质开放。