Derivation and molecular characterization of pancreatic differentiated MODY1-iPSCs
Derivation and molecular characterization of pancreatic differentiated MODY1-iPSCs
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DOI：
10.1016/j.scr.2018.06.013
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发表时间：
2018-08-01
影响因子：
1.2
通讯作者：
Benvenisty, Nissim
中科院分区：
文献类型：
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作者：
Braverman-Gross, Carmel;Nudel, Neta;Benvenisty, Nissim
青年成熟型糖尿病（MODY）是一种在儿童或青少年时期出现的遗传性糖尿病，最终导致胰腺β细胞功能障碍。MODY疾病的潜在遗传基础是单倍不足，其中单个等位基因中的功能缺失突变导致杂合子患者的糖尿病表型。MODY1是一种由转录因子肝细胞核因子4 α（HNF 4 α）突变引起的MODY疾病。为了建立基于人类的模型来研究MODY1，我们产生了患者来源的诱导多能干细胞（iPSC）。这些多能细胞向胰腺谱系的分化使得能够评估MODY1突变的作用及其对内胚层和胰腺细胞的影响。分析分化的MODY1细胞的基因表达谱，揭示了HNF4 α单倍不足对其靶标的影响。该分子分析表明，HNF4 α靶基因在MODY1中的差异表达受HNF4 α结合位点的数量、它们与转录起始位点的距离以及其他转录因子结合位点的数量的影响。这些特征可能有助于解释MODY1疾病单倍不足的分子表现。
Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes mellitus presenting at childhood or adolescence, which eventually leads to pancreatic beta-cells dysfunction. The underlying genetic basis of MODY disorders is haploinsufficiency, where loss-of-function mutations in a single allele cause the diabetic phenotype in heterozygous patients. MODY1 is a type of MODY disorder resulting from a mutation in the transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha). In order to establish a human based model to study MODY1, we generated patient-derived induced pluripotent stem cells (iPSCs). Differentiation of these pluripotent cells towards the pancreatic lineage enabled to evaluate the effects of the MODY1 mutation and its impact on endodermal and pancreatic cells. Analyzing the gene expression profiles of differentiated MODY1 cells, revealed the outcome of HNF4 alpha haploinsufficiency on its targets. This molecular analysis suggests that the differential expression of HNF4 alpha target genes in MODY1 is affected by the number of HNF4 alpha binding sites, their distance from the transcription start site, and the number of other transcription factor binding sites. These features may help explain the molecular manifestations of haploinsufficiency in MODY1 disease.