文章：

多发性骨髓瘤特异性超级增强子影响具有生物学和临床相关性的基因

Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma

原文发布日期：2021-02-12

DOI: 10.1038/s41408-021-00421-7

类型: Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is an aggressive plasma cell neoplasm characterized by genomic heterogeneity. Superenhancers (SEs) are defined as large clusters of enhancers in close genomic proximity, which regulate genes for maintaining cellular identity and promote oncogenic transcription to which cancer cells highly addicted. Here, we analyzed cis-regulatory elements in MM samples with H3K27ac ChIP-seq, to identify novel SE-associated genes involved in the myeloma pathogenesis. SEs and their associated genes in cancerous tissue were compared with the control samples, and we found SE analysis alone uncovered cell-lineage-specific transcription factors and well-known oncogenes ST3GAL6 and ADM. Using a transcriptional CDK7 inhibitor, THZ1, coupled with H3K27ac ChlP-seq, we identified MAGI2 as a novel SE-associated gene of myeloma cells. Elevated MAGI2 was related to myelomagenesis with gradual increased expression from MGUS, SMM to newly diagnosed and relapsed MM. High prevalence of MAGI2 was also associated with poor survival of MM patients. Importantly, inhibition of the SE activity associated with MAGI2 decreased MAGI2 expression, inhibited cell growth and induced cell apoptosis. Mechanistically, we revealed that the oncogenic transcription factor, MAF, directly bound to the SE region and activated gene transcription. In summary, the discoveries of these acquired SEs-associated genes and the novel mechanism by which they are regulated provide new insights into MM biology and MAGI2-MAF-SE regulatory circuit offer potential novel targets for disease treatment.
 

摘要翻译： 

多发性骨髓瘤是一种具有基因组异质性的侵袭性浆细胞肿瘤。超级增强子被定义为基因组邻近区域的大型增强子簇，其调控维持细胞身份的关键基因，并促进癌细胞高度依赖的致癌转录。本研究通过H3K27ac染色质免疫沉淀测序技术分析多发性骨髓瘤样本中的顺式调控元件，以鉴定参与骨髓瘤发病机制的新型超级增强子相关基因。通过比较癌组织与对照样本中的超级增强子及其相关基因，我们发现仅超级增强子分析即可揭示细胞谱系特异性转录因子及已知致癌基因ST3GAL6和ADM。运用转录CDK7抑制剂THZ1结合H3K27ac染色质免疫沉淀测序技术，我们鉴定出MAGI2作为骨髓瘤细胞的新型超级增强子相关基因。MAGI2表达量升高与骨髓瘤发生发展相关，其表达水平从意义未明单克隆丙种球蛋白病、冒烟型骨髓瘤到新诊断及复发骨髓瘤呈现渐进性上升趋势。MAGI2高表达与多发性骨髓瘤患者的不良预后密切相关。重要的是，抑制MAGI2相关超级增强子活性可降低MAGI2表达、抑制细胞生长并诱导细胞凋亡。机制研究表明，致癌转录因子MAF直接结合超级增强子区域并激活基因转录。总之，这些获得性超级增强子相关基因的发现及其调控新机制的阐明，为多发性骨髓瘤生物学提供了新见解，且MAGI2-MAF-SE调控环路为疾病治疗提供了潜在新靶点。

原文链接：

Myeloma-specific superenhancers affect genes of biological and clinical relevance in myeloma