Diabetes Genetic Convergence—Shared Networks of Rare and Common Variants

Monday, June 24, at 3:15 p.m. ET
Room W207
Orange County Convention Center

Single Cell Transcriptomics, Networks, Genetic Convergence, HNF1A

Yan Li, PhD

Associate Professor,
Case Western Reserve University

What is your presentation about?
Broad heterogeneity in pancreatic beta-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 multi-omics from human islets and identify type 2 diabetes-associated beta-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 beta-cells, which reflect distinct mechanisms of type 2 diabetes pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between beta-cells from the same donors; HNF1A expression is also reduced in beta-cells from type 2 diabetes donors. Interestingly, HNF1A activity in single beta-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 type 2 diabetes.

How do you hope your presentation will impact diabetes research or care?
I hope our research and my presentation can introduce a new concept: that there are both “good” and “bad” beta-cells within the same individuals. The transcription factor HNF1A, a MODY3 gene, is the major driver of this beta-cell heterogeneity, which is associated with type 2 diabetes at both transcriptional and epigenetic levels. Using single-cell multiomics data, we have predicted and validated that FXYD2 is a target gene of HNF1A. This gene may play a role in insulin release. Targeting HNF1A or FXYD2 could provide new treatment strategies for MODY3 and type 2 diabetes, as well as offer a potential prevention strategy for type 2 diabetes.

How did you become involved with this area of diabetes research or care?
I am trained as a genomics biologist specializing in transcription regulation within a diabetic context. During my PhD, I investigated the epigenetic regulation of inflammatory responses in atherosclerosis, a common complication of diabetes. In my postdoctoral training, I continued to explore the transcription regulation of inflammation and diabetes-related genes, primarily using genomic and epigenomic approaches. In 2015, I established my lab at Case Western Reserve University with a long-term goal of studying transcription regulation and the functions of non-coding cis-regulatory elements in diabetes. My lab integrates single-cell genomics, epigenomics, and stem cell biology to advance our understanding of diabetes.