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

Broad heterogeneity in pancreatic ß-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 ß-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 ß-cells, which reflect distinct mechanisms of T2D pathogenesis. Integrative transcriptomic and epigenomic analysis identifies HNF1A as a principal driver of intra-donor heterogeneity between ß-cells from the same donors; HNF1A expression is also reduced in ß-cells from T2D donors. Interestingly, HNF1A activity in single ß-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.

DeepLoop robustly maps chromatin interactions from sparse allele-resolved or single-cell Hi-C data at kilobase resolution.

Mapping chromatin loops from noisy Hi-C heatmaps remains a major challenge. Here we present DeepLoop, which performs rigorous bias correction followed by deep-learning-based signal enhancement for robust chromatin interaction mapping from low-depth Hi-C data. DeepLoop enables loop-resolution, single-cell Hi-C analysis. It also achieves a cross-platform convergence between different Hi-C protocols and micrococcal nuclease (micro-C). DeepLoop allowed us to map the genetic and epigenetic determinants of allele-specific chromatin interactions in the human genome. We nominate new loci with allele-specific interactions governed by imprinting or allelic DNA methylation. We also discovered that, in the inactivated X chromosome (Xi), local loops at the DXZ4 'megadomain' boundary escape X-inactivation but the FIRRE 'superloop' locus does not. Importantly, DeepLoop can pinpoint heterozygous single-nucleotide polymorphisms and large structure variants that cause allelic chromatin loops, many of which rewire enhancers with transcription consequences. Taken together, DeepLoop expands the use of Hi-C to provide loop-resolution insights into the genetics of the three-dimensional genome.