Targeting steroid receptor co-activator 3 sensitizes myeloma cell to proteasome inhibitor treatment through NSD2-mediated phase separation and chromatin remodeling [ChIP-Seq]

Functional crosstalk between histone modifications and chromatin remodeling has emerged as a key regulatory mode of transcriptional control during cell fate decisions, but the underlying mechanisms are not fully understood. Here we demonstrate that NSD2/SRC-3 complex coordinates histone H3 lysine 36 dimethylation (H3K36me2) and transcriptional elongation factor Pol II to regulate chromatin dynamic and gene transcription during myeloma resistant to bortezomib. Mechanistically, NSD2 can interact with SRC-3, its SET domain is responsible to H3K36me2 to enhance the transcriptional activity of SRC-3 target gene. The inhibitor of SRC-3, SI-2, can impaired the interaction between NSD2 and SRC-3, caused the distribution of H3K36me2 on the genome-wide. Examination of histone modification in multiple myeloma bortezomib-resistant cell line

组蛋白修饰与染色质重塑之间的功能性串扰，已被证实为细胞命运决定过程中转录调控的核心模式之一，但其背后的具体分子机制尚未完全阐明。本研究证实，NSD2/SRC-3复合物可在硼替佐米耐药多发性骨髓瘤进程中，通过协同调控组蛋白H3赖氨酸36二甲基化（H3K36me2）与转录延伸因子Pol II，进而调节染色质动态变化与基因转录。从分子机制来看，NSD2可与SRC-3发生相互作用，其SET结构域负责介导H3K36me2修饰，以此增强SRC-3靶基因的转录活性。SRC-3抑制剂SI-2可破坏NSD2与SRC-3之间的相互作用，进而影响H3K36me2在全基因组范围内的分布特征。对硼替佐米耐药多发性骨髓瘤细胞系的组蛋白修饰检测