Single cell multiomic analysis reveals diabetes-associated β-cell heterogeneity driven by HNF1A.
Chen WengAnniya GuShanshan ZhangLeina LuLuxin KePeidong GaoXiaoxiao LiuYuntong WangPeinan HuDylan PlummerElise MacDonaldSaixian ZhangJiajia XiSisi LaiKonstantin LeskovKyle YuanFulai JinYan LiPublished in: Nature communications (2023)
Broad 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.
Keyphrases
- single cell
- rna seq
- high throughput
- type diabetes
- cardiovascular disease
- induced apoptosis
- nuclear factor
- genome wide
- glycemic control
- endothelial cells
- gene expression
- poor prognosis
- transcription factor
- dna damage
- stem cells
- metabolic syndrome
- cell proliferation
- adipose tissue
- signaling pathway
- weight loss
- long non coding rna
- inflammatory response
- network analysis