SMARCA3 is a histone H3K23 ubiquitin ligase that regulates H3K9me3 in cancer [ChIP-seq]

Histone ubiquitination is a crucial post-translational modification (PTM) regulating chromatin function, yet many histone ubiquitination sites and their regulatory enzymes remain poorly understood. Here, we identify SMARCA3, a SWI/SNF-related protein frequently downregulated in colorectal cancer (CRC), as an E3 ubiquitin ligase that targets histone H3 at lysine 23 (H3K23). We demonstrate that SMARCA3 histone ubiquitination activity is stimulated by the repressive H3K9me3 mark. Loss of SMARCA3 reduces both H3K23Ub and H3K9me3, increasing chromatin accessibility at promoters and enhancers enriched for pioneer transcription factor motifs. This chromatin ‘rewiring’ alters the transcriptional landscape, driving upregulation of cancer-promoting genes. We validate this mechanism in CRC cell lines and patient-derived organoids, where SMARCA3 loss reduces H3K23Ub and H3K9me3. In xenograft mouse models, overexpression of wild type SMARCA3, but not a RING domain mutant, suppresses tumor growth. Together, our findings define SMARCA3 as a key chromatin regulator contributing to CRC pathogenesis through epigenetic mechanisms. H3K27ac ChIP-seq on three replicates of wildtpye and SMARCA3 KO HEK293T cells

组蛋白泛素化（Histone ubiquitination）是一类关键的翻译后修饰（post-translational modification, PTM），可调控染色质功能，但目前诸多组蛋白泛素化位点及其调控酶的相关机制仍未被充分阐明。本研究鉴定出SMARCA3——一种在结直肠癌（colorectal cancer, CRC）中常发生下调的SWI/SNF相关蛋白——作为靶向组蛋白H3赖氨酸23（H3K23）的E3泛素连接酶（E3 ubiquitin ligase）。我们证实，SMARCA3的组蛋白泛素化活性可被抑制性H3K9me3修饰所激活。SMARCA3缺失会同时降低H3K23泛素化（H3K23Ub）与H3K9me3水平，提升富集先锋转录因子基序的启动子及增强子区域的染色质开放性。这种染色质“重布线”会改变细胞转录谱，驱动促癌基因的表达上调。我们在结直肠癌细胞系及患者来源类器官中验证了该机制，结果显示SMARCA3缺失可降低H3K23Ub与H3K9me3水平。在异种移植小鼠模型中，过表达野生型SMARCA3（而非RING结构域突变体）可抑制肿瘤生长。综上，本研究明确SMARCA3是通过表观遗传机制参与结直肠癌发病的关键染色质调控因子。本数据集包含野生型与SMARCA3敲除（KO）HEK293T细胞的三个生物学重复样本的H3K27ac染色质免疫共沉淀测序（ChIP-seq）数据。