Human Proislet Peptide Promotes Pancreatic Progenitor Cells to Ameliorate Diabetes Through FOXO1/Menin-Mediated Epigenetic Regulation
Human Proislet Peptide Promotes Pancreatic Progenitor Cells to Ameliorate Diabetes Through FOXO1/Menin-Mediated Epigenetic Regulation
复制标题
人胰岛肽通过 FOXO1/Menin 介导的表观遗传调控促进胰腺祖细胞改善糖尿病
DOI：
10.2337/db17-0885
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发表时间：
2018-07-01
期刊：
影响因子：
7.7
通讯作者：
Ma, Xiaosong
中科院分区：
文献类型：
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作者：
Jiang, Zongzhe;Shi, Diwen;Ma, Xiaosong
我们研究了人前列腺肽(HIP)如何调节人胎儿来源的胰岛前体细胞(HFPPC)的分化，并探索了HIP信号与脑膜素通路之间的潜在联系，脑膜素通路是调节胰岛分化的关键。结果表明，HIP可促进胰岛转录因子PDX-1、MAFA和Nkx6.1的表达，以及胰岛素、GLUT2、KIR6.2、SUR1和VDCC等细胞成熟标志的表达。此外，HIP增加了糖尿病小鼠的胰岛素含量，并促进了HFP-PC使血糖正常化的能力。HIP通过增加AKT介导的磷酸化来抑制TFFOXO1。HIP诱导的FOXO1抑制脑膜素的表达，导致脑膜素与三个关键胰岛TF启动子的结合减少，H3K9甲基转移酶SUV39H1的募集减少，从而减少了H3K9me3在启动子上的抑制。这些协同作用导致Proislet TF表达增加，从而诱导HFPPC分化。FOXO1的结构性激活一直阻止HIP诱导的这些转录因子的转录。总而言之，这些研究揭示了HIP/AKT/FOXO/MENIN轴在表观遗传控制糖尿病小鼠胰岛TF表达、调节HFP-PC分化和血糖正常化中的关键作用。
We investigated how human proislet peptide (HIP) regulates differentiation of human fetus-derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of -cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of the HIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice.