Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.
Histone deacetylase regulates insulin signaling via two pathways in pancreatic β cells.
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DOI：
10.1371/journal.pone.0184435
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Kido Y
中科院分区：
文献类型：
--
作者：
Kawada Y;Asahara SI;Sugiura Y;Sato A;Furubayashi A;Kawamura M;Bartolome A;Terashi-Suzuki E;Takai T;Kanno A;Koyanagi-Kimura M;Matsuda T;Hashimoto N;Kido Y
最近的研究表明，胰岛素信号在调节胰腺β细胞质量中起重要作用，其减少被认为与糖尿病的发生有关。然而，胰岛β细胞中胰岛素信号改变的机制尚不清楚。表观遗传控制在糖尿病发病中的作用也有报道。因此，我们分析了胰岛素受体底物2 （IRS2）在MIN6小鼠胰岛素瘤细胞系中表达的表观遗传控制。我们在MIN6细胞中发现IRS2上调和胰岛素信号传导增强，导致细胞增殖增加。Irs2启动子的H3K9乙酰化状态与Irs2表达呈正相关。用组蛋白去乙酰化酶抑制剂处理MIN6细胞导致IRS2表达增加，但这与低胰岛素信号一致。我们观察到，由于组蛋白去乙酰化酶抑制，IRS2赖氨酸乙酰化增加，这种修饰与IRS2酪氨酸磷酸化减少相结合。这些结果表明，胰腺β细胞中的胰岛素信号是由组蛋白去乙酰化酶通过两种影响IRS2的新途径调控的：通过H3K9启动子乙酰化调控IRS2表达的表观遗传调控，以及通过蛋白修饰调控IRS2活性。鉴定参与这些机制的组蛋白去乙酰化酶异构体将是治疗2型糖尿病的一个有价值的方法。
Recent studies demonstrated that insulin signaling plays important roles in the regulation of pancreatic β cell mass, the reduction of which is known to be involved in the development of diabetes. However, the mechanism underlying the alteration of insulin signaling in pancreatic β cells remains unclear. The involvement of epigenetic control in the onset of diabetes has also been reported. Thus, we analyzed the epigenetic control of insulin receptor substrate 2 (IRS2) expression in the MIN6 mouse insulinoma cell line. We found concomitant IRS2 up-regulation and enhanced insulin signaling in MIN6 cells, which resulted in an increase in cell proliferation. The H3K9 acetylation status of the Irs2 promoter was positively associated with IRS2 expression. Treatment of MIN6 cells with histone deacetylase inhibitors led to increased IRS2 expression, but this occurred in concert with low insulin signaling. We observed increased IRS2 lysine acetylation as a consequence of histone deacetylase inhibition, a modification that was coupled with a decrease in IRS2 tyrosine phosphorylation. These results suggest that insulin signaling in pancreatic β cells is regulated by histone deacetylases through two novel pathways affecting IRS2: the epigenetic control of IRS2 expression by H3K9 promoter acetylation, and the regulation of IRS2 activity through protein modification. The identification of the histone deacetylase isoform(s) involved in these mechanisms would be a valuable approach for the treatment of type 2 diabetes.
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影响因子：
3.7
作者：
Liu Z;Kim W;Chen Z;Shin YK;Carlson OD;Fiori JL;Xin L;Napora JK;Short R;Odetunde JO;Lao Q;Egan JM
通讯作者：
Egan JM
影响因子：
3.3
作者：
Doi, Toshihiko;Hamaguchi, Tetsuya;Ohtsu, Atsushi
通讯作者：
Ohtsu, Atsushi
DOI：
10.1016/j.bbrc.2009.02.047
发表时间：
2009-04-10
影响因子：
3.1
作者：
Asahara, Shun-ichiro;Matsuda, Tomokazu;Kasuga, Masato
通讯作者：
Kasuga, Masato
DOI：
10.1073/pnas.0705667104
发表时间：
2007-07-31
影响因子：
11.1
作者：
Gluckman, Peter D.;Lillycrop, Karen A.;Hanson, Mark A.
通讯作者：
Hanson, Mark A.
影响因子：
8.2
作者：
Asahara, S.;Shibutani, Y.;Teruyama, K.;Inoue, H. Y.;Kawada, Y.;Etoh, H.;Matsuda, T.;Kimura-Koyanagi, M.;Hashimoto, N.;Sakahara, M.;Fujimoto, W.;Takahashi, H.;Ueda, S.;Hosooka, T.;Satoh, T.;Inoue, H.;Matsumoto, M.;Aiba, A.;Kasuga, M.;Kido, Y.
通讯作者：
Kido, Y.