Single cell multi-omics analysis deconstructs diabetes-associated ß-cell heterogeneity in human islets
The functional heterogeneity of ß-cells is important for metabolism and diseases, but the nature and mechanism of such variation at molecular level remain elusive. Here we explore this question by comparing both single cell RNA-seq and single cell ATAC-seq maps of healthy and type II diabetic (T2D) human islets. We dissect the T2D-associated single cell trajectory and identified signature genes and enhancers in ß-cells. We also map the 3D genome of both a- and ß-cells with low-input eHi-C approach to unravel the cell type-specific gene regulatory circuits. Strikingly, more than one third of the T2D signature genes show significant intra-donor heterogeneity at single cell level; these genes are functionally distinct from other signature genes that are largely invariant among cells from the same individual but differentially expressed between donors, suggesting different roles in T2D pathogenesis. Importantly, we identified consistent intra-donor variations at both transcriptomic and epigenomic levels, which strongly support the heterogenous ß-cell states and transcription programs. Finally, we construct the disease-signature regulatory networks and pinpointed HNF1A as one of the top transcription factors governing T2D-associated ß-cell heterogeneity. Taken together, we provide the first multi-omic characterization of ß-cell heterogeneity and reveals its connection to T2D. Overall design: HNF1A CUT&RUN in EndoC-BH3 cell line, 600k cell in total, antibody is abcam cat#:ab204306