SIRT6 介导的 Txnip 转录抑制对于小鼠胰岛β细胞功能和存活至关重要。
SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice.
机构信息
Department of Molecular Medicine, University of Texas Health Science Centre at San Antonio, San Antonio, TX, USA.
Department of Cell Systems & Anatomy, University of Texas Health Science Centre at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
出版信息
Diabetologia. 2018 Apr;61(4):906-918. doi: 10.1007/s00125-017-4542-6. Epub 2018 Jan 10.
AIMS/HYPOTHESIS: Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis.
METHODS
Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-Seq analysis. Reverse transcription-quantitative (RT-q)PCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac and active RNA polymerase II were evaluated by chromatin immunoprecipitation.
RESULTS
Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass or insulin production but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of thioredoxin-interacting protein (TXNIP) in beta cells. SIRT6 deficiency led to increased acetylation of histone H3 lysine residue at 9 (H3K9Ac), acetylation of histone H3 lysine residue at 56 (H3K56Ac) and active RNA polymerase II at the promoter region of Txnip. SIRT6-deficient beta cells exhibited a time-dependent increase in H3K9Ac, H3K56Ac and TXNIP levels. Finally, beta cell-specific SIRT6-deficient mice showed increased sensitivity to streptozotocin.
CONCLUSIONS/INTERPRETATION: Our results reveal that SIRT6 suppresses Txnip expression in beta cells via deacetylation of histone H3 and plays a critical role in maintaining beta cell function and viability.
DATA AVAILABILITY
Sequence data have been deposited in the National Institutes of Health (NIH) Gene Expression Omnibus (GEO) with the accession code GSE104161.
目的/假设：更好地了解遗传和表观遗传成分如何控制β细胞分化和功能是发现预防 2 型糖尿病进展中β细胞功能障碍和衰竭的新治疗方法的关键。我们的目标是阐明组蛋白去乙酰化酶 Sirtuin 6（SIRT6）在β细胞发育和稳态中的作用。
方法
使用 Cre-loxP 系统生成 Sirt6 内分泌祖细胞条件性敲除和β细胞特异性敲除小鼠。通过胰岛形态、葡萄糖耐量、葡萄糖刺激胰岛素分泌和链脲佐菌素易感性检测评估小鼠。通过 RNA-Seq 分析评估 SIRT6 在原代胰岛中的转录调控功能。逆转录定量（RT-q）PCR 和免疫印迹用于验证和研究基因表达变化。通过染色质免疫沉淀评估 SIRT6、H3K9Ac、H3K56Ac 和活性 RNA 聚合酶 II 的染色质占有率。
结果
胰腺内分泌祖细胞中 Sirt6 的缺失不影响内分泌形态、β细胞质量或胰岛素产生，但导致小鼠葡萄糖耐量受损和葡萄糖刺激胰岛素分泌缺陷。成年β细胞中 Sirt6 的条件性缺失再现了胰岛素分泌缺陷。Sirt6 的缺失导致β 细胞中硫氧还蛋白相互作用蛋白（TXNIP）的异常上调。SIRT6 缺乏导致 TXNIP 启动子区域组蛋白 H3 赖氨酸残基 9（H3K9Ac）、组蛋白 H3 赖氨酸残基 56（H3K56Ac）和活性 RNA 聚合酶 II 的乙酰化增加。SIRT6 缺陷的β 细胞表现出 TXNIP 水平的时间依赖性增加。最后，β 细胞特异性 SIRT6 缺陷小鼠对链脲佐菌素的敏感性增加。
结论/解释：我们的结果表明，SIRT6 通过组蛋白 H3 的去乙酰化抑制β 细胞中 TXNIP 的表达，并在维持β 细胞功能和活力方面发挥关键作用。
数据可用性
序列数据已在国立卫生研究院（NIH）基因表达综合数据库（GEO）中以注册号 GSE104161 进行了存储。
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