期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 1, 页码 230-243出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI88015
关键词
-
资金
- Juvenile Diabetes Research Foundation (JDRF)
- Beta Cell Biology Consortium
- Human Islet Research Network of the NIH [DK104216]
- Helmsley Charitable Trust
- European Research Commission (ERC consolidator grant)
- Britain Israel Research and Academic Exchange Partnership (BIRAX)
- Diabetes Onderzoek Nederland (DON) Foundation
- Israel Science Foundation
- I-CORE Program of The Israel Science Foundation (ISF) [41.11]
- Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project - JDRF
- USAID's American Schools and Hospitals Abroad Program
- United States-Israel Binational Science Foundation (BSF) [2013016]
- ISF [228/14]
- Adams Foundation
- Ariane de Rothschild Women Doctoral Program
- The British Council [14BX14NHBG] Funding Source: researchfish
Type 2 diabetes is thought to involve a compromised beta cell differentiation state, but the mechanisms underlying this dysfunction remain unclear. Here, we report a key role for the TF PAX6 in the maintenance of adult beta cell identity and function. PAX6 was downregulated in beta cells of diabetic db/db mice and in WT mice treated with an insulin receptor antagonist, revealing metabolic control of expression. Deletion of Pax6 in beta cells of adult mice led to lethal hyperglycemia and ketosis that were attributed to loss of beta cell function and expansion of a cells. Lineage-tracing, transcriptome, and chromatin analyses showed that PAX6 is a direct activator of beta cell genes, thus maintaining mature beta cell function and identity. In parallel, we found that PAX6 binds promoters and enhancers to repress alternative islet cell genes including ghrelin, glucagon, and somatostatin. Chromatin analysis and shRNA-mediated gene suppression experiments indicated a similar function of PAX6 in human beta cells. We conclude that reduced expression of PAX6 in metabolically stressed beta cells may contribute to beta cell failure and a cell dysfunction in diabetes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据