Schwaemmle Hanna, Soldati Hadrien, Lykoskoufis Nikolaos M R, Docquier Mylène, Hainard Alexandre, Braun Simon M G
Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Institute of Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva, Switzerland.
Nat Commun. 2025 May 30;16(1):5011. doi: 10.1038/s41467-025-60424-x.
The SWI/SNF (or BAF) complex is an essential chromatin remodeler, which is frequently mutated in cancer and neurodevelopmental disorders. These are often heterozygous loss-of-function mutations, indicating a dosage-sensitive role for SWI/SNF subunits. However, the molecular mechanisms regulating SWI/SNF subunit dosage to ensure complex assembly remain largely unexplored. We performed a CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, promotes SWI/SNF assembly and binding to chromatin. Rapid degradation of MLF2 reduces chromatin accessibility at sites that depend on high levels of SWI/SNF binding to maintain open chromatin. Next, we find that RBM15, part of the mA writer complex, controls mA modifications on specific SWI/SNF mRNAs to regulate subunit protein levels. Misregulation of mA methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
SWI/SNF（或BAF）复合体是一种重要的染色质重塑因子，在癌症和神经发育障碍中经常发生突变。这些突变通常是杂合性功能丧失突变，表明SWI/SNF亚基具有剂量敏感性作用。然而，调节SWI/SNF亚基剂量以确保复合体组装的分子机制在很大程度上仍未被探索。我们利用小鼠胚胎干细胞中的表观基因组编辑进行了CRISPR敲除筛选，并确定Mlf2和Rbm15是SWI/SNF复合体活性的调节因子。首先，我们表明MLF2是一种特征不明的伴侣蛋白，它促进SWI/SNF组装并与染色质结合。MLF2的快速降解会降低依赖高水平SWI/SNF结合来维持开放染色质的位点的染色质可及性。接下来，我们发现作为mA书写复合体一部分的RBM15控制特定SWI/SNF mRNA上的mA修饰，以调节亚基蛋白水平。mA甲基化失调会导致核心SWI/SNF亚基的过表达，从而导致缺乏催化性ATP酶/ARP亚基的不完整复合体的组装。这些数据表明，靶向SWI/SNF复合体组装的调节因子可能为与染色质重塑受损相关的疾病提供一种有效的治疗策略。
