Transcriptional dysregulation of BAHCC1 in melanoma [RNA-seq]. Transcriptional dysregulation of BAHCC1 in melanoma [RNA-seq]

Transcriptional addiction of cancer cells for Super-Enhancer (SE) associated genes has been proven through an extensive use of transcriptional inhibitors against specific co-activators toward which SE are esponentially dependent compared to canonical enhancers. However, each cancer type displays different sensitivity against this new class of drugs whose efficacy may vary according to their transcriptomic profile including the expression of enzymatic proteins able to confer intrinsic tolerance or resistance. Moreover, SE has been observed as well in healthy cells which point a realistic concern toward the specificity of transcriptional inhibitors and their side effects on healthy tissues. Therefore, we looked at SE-associated genes specific for cancer using melanoma as a model. Here, we identified BAHCC1 whose activity is higher in melanoma compare to other cancer types and normal tissues. BAHCC1 is a protein involved both in gene expression and genomic stability. To explore BAHCC1 role in gene expression, we performed functional studies in melanoma cells in basal conditions or upon BAHCC1 silencing. Strikingly, BAHCC1 regulates an E2F-dependent subset of genes together with SWI/SNF chromatin remodelling complex. Overall design: Total RNA sequencing

癌细胞对于超级增强子（Super-Enhancer, SE）关联基因的转录成瘾性，已通过大量使用针对特定共激活因子的转录抑制剂得到证实——相较于经典增强子，超级增强子对这类共激活因子的依赖性呈指数级增长。然而，不同癌症类型对这类新型药物的敏感性存在差异，其疗效可随肿瘤的转录组特征（包括能够赋予内在耐受或耐药性的酶蛋白表达水平）发生变化。此外，研究还在健康细胞中发现了超级增强子的存在，这引发了人们对转录抑制剂特异性及其对健康组织副作用的切实担忧。因此，本研究以黑色素瘤为模型，探究癌症特异性的超级增强子关联基因。本研究鉴定出BAHCC1，相较于其他癌症类型与正常组织，该蛋白在黑色素瘤中的表达活性更高。BAHCC1是一种同时参与基因表达调控与基因组稳定性维持的蛋白质。为探究BAHCC1在基因表达调控中的作用，本研究在基础培养条件下或经BAHCC1基因沉默后的黑色素瘤细胞中开展了功能实验。令人意外的是，BAHCC1与SWI/SNF染色质重塑复合体共同调控依赖于E2F的基因子集。整体实验设计：总RNA测序