2019年8月出版的《细胞—干细胞》发表了美国科学家的一项最新研究成果。来自费城儿童医院的Paul Gadue团队提出了利用人类ESCs建模单基因糖尿病，揭示了HNF1A突变引起的发育和代谢缺陷。

研究组通过基因组编辑人类胚胎干细胞，进而了解最常见的单基因型糖尿病-MODY3（转录因子HNF1A突变导致）。该研究组发现HNF1A对于抑制α细胞基因表达特征、维持内分泌细胞功能、和调节细胞代谢是必不可少的。此外，该团队还确定了人类特有的长链非编码RNA—LINKA，为HNF1A的一个靶标，是正常线粒体呼吸所必需的。这些发现为HNF1A突变引起的疾病表型中所观测到的种间差异，提供了可能的解释，并为HNF1A基因如何影响2型糖尿病提供了机制上的见解。

据介绍，人类单基因糖尿病是一种基因突变引起的疾病，涉及β细胞发育和功能，由于多种小鼠模型还没有完全再现人类疾病，因此该疾病一直是研究的一大挑战。

附：英文原文

Title: Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A

Author: Fabian L. Cardenas-Diaz, Catherine Osorio-Quintero, Maria A. Diaz-Miranda, Siddharth Kishore, Karla Leavens, Chintan Jobaliya, Diana Stanescu, Xilma Ortiz-Gonzalez, Christine Yoon, Christopher S. Chen, Rachana Haliyur, Marcela Brissova, Alvin C. Powers, Deborah L. French, Paul Gadue

Issue&Volume: Volume 25 Issue 2

Abstract: 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 mitochondrial 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.

DOI: https://doi.org/10.1016/j.stem.2019.07.007

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30305-4