Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2021 May 12;12(5):476. doi: 10.1038/s41419-021-03761-1.
Loss of β cell identity and functional immaturity are thought to be involved in β cell failure in type 2 diabetes. CREB-binding protein (CBP) and its paralogue p300 act as multifunctional transcriptional co-activators and histone acetyltransferases (HAT) with extensive biological functions. However, whether the regulatory role of CBP/p300 in islet β cell function depends on the HAT activity remains uncertain. In this current study, A-485, a selective inhibitor of CBP/p300 HAT activity, greatly impaired glucose-stimulated insulin secretion from rat islets in vitro and in vivo. RNA-sequencing analysis showed a comprehensive downregulation of β cell and α cell identity genes in A-485-treated islets, without upregulation of dedifferentiation markers and derepression of disallowed genes. A-485 treatment decreased the expressions of genes involved in glucose sensing, not in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. In the islets of prediabetic db/db mice, CBP/p300 displayed a significant decrease with key genes for β cell function. The deacetylation of histone H3K27 as well as the transcription factors Hnf1α and Foxo1 was involved in CBP/p300 HAT inactivation-repressed expressions of β cell identity and functional genes. These findings highlight the dominant role of CBP/p300 HAT in the maintenance of β cell identity by governing transcription network.
β 细胞表型丧失和功能不成熟被认为与 2 型糖尿病中的β 细胞衰竭有关。CREB 结合蛋白 (CBP) 和其同源物 p300 作为多功能转录共激活因子和组蛋白乙酰转移酶 (HAT)，具有广泛的生物学功能。然而，CBP/p300 对胰岛β细胞功能的调节作用是否依赖于 HAT 活性尚不确定。在本研究中，CBP/p300 HAT 活性的选择性抑制剂 A-485 极大地损害了大鼠胰岛体外和体内的葡萄糖刺激胰岛素分泌。RNA-seq 分析显示，A-485 处理的胰岛中β 细胞和α 细胞特征基因全面下调，而未分化标志物未上调，禁止基因未去抑制。A-485 处理降低了参与葡萄糖感应的基因的表达，而不是糖酵解、三羧酸循环和氧化磷酸化的基因。在糖尿病前期 db/db 小鼠的胰岛中，CBP/p300 表达显著降低，与β 细胞功能的关键基因降低有关。组蛋白 H3K27 的去乙酰化以及转录因子 Hnf1α 和 Foxo1 参与了 CBP/p300 HAT 失活-抑制β 细胞特征和功能基因的表达。这些发现强调了 CBP/p300 HAT 通过调节转录网络在维持β 细胞表型中的主导作用。
