Pharmacological HDAC inhibition impairs pancreatic ß-cell function through a genome-wide epigenomic reprogramming [RNA-seq]

Histone deacetylases (HDAC) enzymes are chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic b cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic b-cell identity and function using trichostatin A (TSA), a pan-HDAC inhibitor. We observed that TSA alters insulin secretion associated with b-cell specific transcriptome programming in both mouse and human b-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative b-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of ß-cell identity with unsuitable expression of genes associated with alternative cell fates. Overall design: Transcriptomic profiling of TSA-treated Min6 cells, mouse beta cell sorted, EndoCbH1 cells and human islets of Langerhans

组蛋白去乙酰化酶（Histone deacetylases，HDAC）是一类染色质修饰酶，通过对特定组蛋白与非组蛋白内的赖氨酸残基进行去乙酰化修饰，直接调控基因表达。产胰岛素的胰腺β细胞的身份由细胞特异性基因表达模式决定，但调控该转录特异性的分子网络尚未完全明晰。本研究使用泛HDAC抑制剂曲古抑菌素A（trichostatin A，TSA），探究了调控胰腺β细胞身份与功能的HDAC依赖性分子机制。我们观察到，在小鼠与人类β细胞系以及人胰腺胰岛中，TSA均可改变与β细胞特异性转录组编程相关的胰岛素分泌。本研究还证实，HDAC抑制所诱导的β细胞替代性转录程序，与启动子和增强子区域的全表观基因组重塑密切相关。我们的数据表明，完整的HDAC活性对于维持表观基因组稳态、防止β细胞身份丧失以及避免与替代性细胞命运相关基因的异常表达至关重要。整体实验设计：对经TSA处理的Min6细胞、分选的小鼠β细胞、EndoCbH1细胞以及人胰岛进行转录组分析（Transcriptomic profiling）。