HDAC1 regulates the chromatin landscape to control transcriptional dependencies in chronic lymphocytic leukemia [miRNA-seq]

Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome wide occupancy of HDAC1, BRD4, H3K27Ac and H3K9Ac signals with chromatin accessibility, Pol2 occupancy and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression in CLL. Targeting HDACs reduced BRD4 and Pol2 engagement to downregulate the transcript and proteins levels of specific oncogenic driver genes in CLL such as BLK, a key mediator of the B-cell receptor pathway, core transcription factors such as PAX5 and IKZF3 and the anti-apoptotic gene, BCL2. Concurrently, HDAC1, when recruited in the absence of super-enhancers repressed target gene expression. HDAC inhibition reversed silencing of a defined set of protein coding and noncoding RNA genes. We focused on a specific set of microRNA genes and show that their upregulation was inversely correlated with the expression of CLL specific survival, transcription factor and signaling genes. Our findings identify that the transcriptional activator and repressor functions of HDACs cooperate within the same tumor to establish the transcriptional dependencies essential for survival in CLL. miRNA-seq

慢性淋巴细胞白血病（chronic lymphocytic leukemia, CLL）是一种静息态B细胞恶性肿瘤，其存活依赖于转录失调。组蛋白去乙酰化酶（histone deacetylases, HDACs）是一类转录调控因子，但其在调控性染色质中的作用以及对CLL转录组的影响尚未得到充分阐明。本研究对CLL细胞中HDAC1、BRD4、H3K27Ac及H3K9Ac的全基因组结合信号进行了图谱绘制，并将其与染色质开放性、RNA聚合酶II（RNA polymerase II, Pol2）结合特征以及靶基因表达特征进行整合分析。本研究发现，当HDAC1被招募至以乙酰化H3K27和BRD4标记的超级增强子（super-enhancers, SEs）区域时，其可作为转录激活因子，驱动特定基因的从头表达，进而促进CLL的存活与进展。靶向抑制HDACs可降低BRD4与Pol2的结合，从而下调CLL中特定致癌驱动基因的转录本及蛋白水平，例如B细胞受体通路关键介导因子BLK、核心转录因子PAX5与IKZF3，以及抗凋亡基因BCL2。与此同时，当HDAC1被招募至不含超级增强子的区域时，可抑制靶基因的表达。HDAC抑制剂处理可逆转特定编码蛋白基因与非编码RNA基因的沉默状态。本研究聚焦于特定的微小RNA（microRNA, miRNA）基因集，发现其表达上调与CLL特异性存活相关基因、转录因子及信号通路基因的表达呈负相关。本研究结果表明，HDACs的转录激活与抑制功能在同一肿瘤内协同作用，从而构建CLL存活所必需的转录依赖特性。miRNA-seq