PT - JOURNAL ARTICLE AU - Vivek Rai AU - Daniel X. Quang AU - Michael R. Erdos AU - Darren A. Cusanovich AU - Riza M. Daza AU - Narisu Narisu AU - Luli S. Zou AU - John P. Didion AU - Yuanfang Guan AU - Jay Shendure AU - Stephen C.J. Parker AU - Francis S. Collins TI - Single cell ATAC-seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures AID - 10.1101/749283 DP - 2019 Jan 01 TA - bioRxiv PG - 749283 4099 - http://biorxiv.org/content/early/2019/09/07/749283.short 4100 - http://biorxiv.org/content/early/2019/09/07/749283.full AB - Objective Type 2 diabetes (T2D) is a complex disease characterized by pancreatic islet dysfunction, insulin resistance, and disruption of blood-glucose levels. Genome-wide association studies (GWAS) have identified >400 independent signals that encode genetic predisposition. More than 90% of the associated single nucleotide polymorphisms (SNPs) localize to non-coding regions and are enriched in chromatin-defined islet enhancer elements, indicating a strong regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types expressing distinct hormonal programs, and so each cell type may contribute differentially to the underlying regulatory processes that modulate T2D-associated transcriptional circuits. Existing chromatin profiling methods such as ATAC-seq and DNase-seq, applied to islets in bulk, produce aggregate profiles that mask important cellular and regulatory heterogeneity.Methods We present genome-wide single cell chromatin accessibility profiles in >1,600 cells derived from a human pancreatic islet sample using single-cell-combinatorial-indexing ATAC-seq (sci-ATAC-seq). We also developed a deep learning model based on the U-Net architecture to accurately predict open chromatin peak calls in rare cell populations.Results We show that sci-ATAC-seq profiles allow us to deconvolve alpha, beta, and delta cell populations and identify cell-type-specific regulatory signatures underlying T2D. Particularly, we find that T2D GWAS SNPs are significantly enriched in beta cell-specific and cross cell-type shared islet open chromatin, but not in alpha or delta cell-specific open chromatin. We also demonstrate, using less abundant delta cells, that deep-learning models can improve signal recovery and feature reconstruction of rarer cell-populations. Finally, we use co-accessibility measures to nominate the cell-specific target genes at 104 non-coding T2D GWAS signals.Conclusions Collectively, we identify the islet cell-type of action across genetic signals of T2D predisposition and provide higher-resolution mechanistic insights into genetically encoded risk pathways.(ATAC-seq)Assay for Transposase Accessible Chromatin Sequencing(GWAS)Genome wide association study(eQTL)Expression quantitative trait loci(GCG)Glucagon(INS)Insulin(SST)Somatostatin.