FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression
FCoR-Foxo1 Axis Regulates α-Cell Mass through Repression of Arx Expression
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DOI：
10.1016/j.isci.2019.100798
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发表时间：
2020-01-24
期刊：
影响因子：
5.8
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Kodani, Noriko;Nakae, Jun;Itoh, Hiroshi
胰腺内分泌细胞向分化的α和β细胞的发育受到高度调控，并涉及多种转录因子。然而，阿尔法和贝塔细胞质量测定背后的机制仍不清楚。我们先前发现了Foxo1辅阻遏子(FCoR)，它通过乙酰化来抑制Foxo1。在这里，我们证明了FcoR基因敲除小鼠(FcorKO)表现出显著的阿尔法细胞质量增加，主要的阿尔法细胞调节因子无Aristaless相关同源框(ARX)的表达，这可以通过β细胞特异性的FCoR过度表达(FcorKO-βFcor)来正常化，并表现出β细胞到α细胞的转换。与FcorKO相比，FcorKO(DKO)中的β细胞特异性Foxol基因敲除导致Arx表达和α细胞质量下降。Foxol与Arx启动子结合后，DNA甲基转移酶3a(DNMT3A)解离，Arx启动子低甲基化，Arx表达增加。相反，FCoR通过抑制Foxol和DNMT3A对Arx启动子的募集而抑制Arx，并增加Arx启动子的甲基化。我们的发现表明，FCoR-Foxo1轴通过抑制Arx的表达来调节胰腺α细胞质量。
Pancreatic endocrine cell development into differentiated alpha- and beta-cells is highly regulated and involves multiple transcription factors. However, the mechanisms behind the determination of alpha- and beta-cell masses remains unclear. We previously identified Foxo1 CoRepressor (FCoR), which inhibits Foxo1 by acetylation. Here we demonstrate that Fcor-knockout mice (FcorKO) exhibit significantly increased alpha-cell mass, expression of the master alpha-cell regulatory transcription factor Aristaless-related homeobox (Arx), which can be normalized by beta-cell-specific FCoR overexpression (FcorKO-beta Fcor), and exhibit beta-to-alpha-cell conversion. Compared with FcorKO, beta-cell-specific Foxol knockout in the FcorKO (DKO) led to decreased Arx expression and a-cell mass. Foxol binding to Arx promoter led to DNA methyltransferase 3a (Dnmt3a) dissociation, Arx promoter hypomethylation, and increased Arx expression. In contrast, FCoR suppressed Arx through Foxol inhibition and Dnmt3a recruitment to Arx promoter and increased Arx promoter methylation. Our findings suggest that the FCoR-Foxo1 axis regulates pancreatic alpha-cell mass by suppressing Arx expression.