Rxivist logo

Single cell ATAC-seq in human pancreatic islets and deep learning upscaling of rare cells reveals cell-specific type 2 diabetes regulatory signatures

By Vivek Rai, Daniel X. Quang, Michael R Erdos, Darren A. Cusanovich, Riza M. Daza, Narisu Narisu, Luli S. Zou, John P Didion, Yuanfang Guan, Jay Shendure, Stephen C.J. Parker, Francis S Collins

Posted 07 Sep 2019
bioRxiv DOI: 10.1101/749283 (published DOI: 10.1016/j.molmet.2019.12.006)

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 transcriptional regulatory component to disease susceptibility. Pancreatic islets are a mixture of cell types that express 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.

Download data

  • Downloaded 1,776 times
  • Download rankings, all-time:
    • Site-wide: 10,166
    • In genomics: 1,062
  • Year to date:
    • Site-wide: 99,320
  • Since beginning of last month:
    • Site-wide: 126,834

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News