Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A

Author:

Weng Chen,Gu Anniya,Zhang Shanshan,Lu Leina,Ke LuxinORCID,Gao Peidong,Liu XiaoxiaoORCID,Wang YuntongORCID,Hu Peinan,Plummer Dylan,MacDonald EliseORCID,Zhang Saixian,Xi Jiajia,Lai SisiORCID,Leskov KonstantinORCID,Yuan Kyle,Jin FulaiORCID,Li YanORCID

Abstract

AbstractBroad heterogeneity in pancreatic β-cell function and morphology has been widely reported. However, determining which components of this cellular heterogeneity serve a diabetes-relevant function remains challenging. Here, we integrate single-cell transcriptome, single-nuclei chromatin accessibility, and cell-type specific 3D genome profiles from human islets and identify Type II Diabetes (T2D)-associated β-cell heterogeneity at both transcriptomic and epigenomic levels. We develop a computational method to explicitly dissect the intra-donor and inter-donor heterogeneity between single β-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between β-cells from the same donors; HNF1A expression is also reduced in β-cells from T2D donors. Interestingly, HNF1A activity in single β-cells is significantly associated with lower Na+ currents and we nominate a HNF1A target, FXYD2, as the primary mitigator. Our study demonstrates the value of investigating disease-associated single-cell heterogeneity and provides new insights into the pathogenesis of T2D.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

Case Western Reserve University School of Medicine | Clinical and Translational Science Collaborative of Cleveland, School of Medicine, Case Western Reserve University

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Cancer Institute

U.S. Department of Health & Human Services | NIH | National Institute on Aging

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3