Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A
Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A
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DOI：
10.1016/j.stem.2019.07.007
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发表时间：
2019-08-01
期刊：
影响因子：
23.9
通讯作者：
Gadue, Paul
中科院分区：
文献类型：
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作者：
Cardenas-Diaz, Fabian L.;Osorio-Quintero, Catherine;Gadue, Paul
人类单基因糖尿病是由参与β细胞发育和功能的基因突变引起的，一直是研究的挑战，因为多种小鼠模型尚未完全重现人类疾病。在这里，我们使用基因组编辑的人类胚胎干细胞来了解由转录因子HNF 1A突变引起的最常见的单基因糖尿病MODY 3。我们发现HNF 1A是抑制α细胞基因表达特征、维持内分泌细胞功能和调节细胞代谢所必需的。此外，我们鉴定了人类特异性长非编码RNA，LINKA，作为正常线粒体所必需的HNF 1A靶标！呼吸这些发现为HNF 1A突变观察到的疾病表型的物种差异提供了可能的解释，并为HNF 1A基因如何影响2型糖尿病提供了机制见解。
Human monogenic diabetes, caused by mutations in genes involved in beta cell development and function, has been a challenge to study because multiple mouse models have not fully recapitulated the human disease. Here, we use genome edited human embryonic stem cells to understand the most common form of monogenic diabetes, MODY3, caused by mutations in the transcription factor HNF1A. We found that HNF1A is necessary to repress an alpha cell gene expression signature, maintain endocrine cell function, and regulate cellular metabolism. In addition, we identified the human-specific long non-coding RNA, LINKA, as an HNF1A target necessary for normal mitochondria! respiration. These findings provide a possible explanation for the species difference in disease phenotypes observed with HNF1A mutations and offer mechanistic insights into how the HNF1A gene may also influence type 2 diabetes.