Selective Disruption of Core Regulatory Transcription [single cell RNA-seq]

Activation of identity determining transcription factors (TFs), or core regulatory TFs, is governed by cell-type specific enhancers, an important subset of these being super enhancers (SEs). This mechanism is distinct from constitutive expression of housekeeping genes. The characterization of drug-like small molecules to selectively inhibit core regulatory circuitry is of high interest for treatment of cancers, which are addicted to core regulatory TF function at SEs. Surprisingly, we find histone deacetylases (HDAC) to be an indispensable component of SE-driven transcription. While histone acetylation is a marker for active genes, over accumulation of acetylation selectively halts core regulatory transcription. We show this conundrum may in part be explained by a SE-specific need for resetting histones to maintain SE boundaries, to facilitate enhancer-promoter looping and high levels of transcription. Overall design: Single cell RNA-seq data for FP-RMS cells treated with Entinostat.

身份决定转录因子（transcription factors, TFs），又称核心调控转录因子，其激活过程受细胞类型特异性增强子调控，其中这类增强子的一个重要子集为超级增强子（super enhancers, SEs）。该机制与管家基因的组成型表达模式截然不同。
开发可选择性抑制核心调控环路（core regulatory circuitry）的类药物小分子，对于治疗依赖超级增强子处核心调控转录因子功能的癌症具有重要研究价值。令人意外的是，我们发现组蛋白去乙酰化酶（histone deacetylases, HDAC）是超级增强子驱动的转录过程中不可或缺的组成部分。尽管组蛋白乙酰化（histone acetylation）是活跃基因的标志性修饰，但乙酰化的过度积累会选择性地阻断核心调控转录过程。我们的研究表明，这一悖论可部分通过超级增强子特异性的组蛋白重置需求得以解释：该需求用于维持超级增强子的边界，以促进增强子-启动子环化（enhancer-promoter looping）与高水平转录。
整体实验设计：经恩替诺特（Entinostat）处理的融合阳性横纹肌肉瘤（FP-RMS）细胞的单细胞RNA测序（single cell RNA-seq）数据。