A Chromatin Basis for Cell Lineage and Disease Risk in the Human Pancreas

Abstract

Understanding the genomic logic that underlies cellular diversity and developmental potential in the human pancreas will accelerate the growth of cell replacement therapies and reveal genetic risk mechanisms in diabetes. Here, we identified and characterized thousands of chromatin regions governing cell-specific gene regulation in human pancreatic endocrine and exocrine lineages, including islet β cells, α cells, duct, and acinar cells. Our findings have captured cellular ontogenies at the chromatin level, identified lineage-specific regulators potentially acting on these sites, and uncovered hallmarks of regulatory plasticity between cell types that suggest mechanisms to regenerate β cells from pancreatic endocrine or exocrine cells. Our work shows that disease risk variants related to pancreas are significantly enriched in these regulatory regions and reveals previously unrecognized links between endocrine and exocrine pancreas in diabetes risk.

The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes

“…Importantly, we show that such regulatory changes are coupled with 3D chromatin remodeling, allowing the newly activated regulatory elements to contact their target genes. Several reports described 3D chromatin dynamics properties in the cell developmental context 33,34 , upon loss of cell fate 35,36 , senescence 37,38 or in response to hormonal exposure 39 . Our observations indicate that the capacity of enhancer loop formation is maintained in a highlydifferentiated tissue such as the islets and it is coupled with transcriptional regulatory changes, in response to an external stimulus.…”

“…Such model is supported by very recent findings 30 and consistent with observations in murine macrophages 7,31 and murine dendritic cells 32 , but thus far had not been demonstrated in a highly differentiated and nonimmune related tissue such as the pancreatic islets.Importantly, we show that such regulatory changes are coupled with 3D chromatin remodeling, allowing the newly activated regulatory elements to contact their target genes. Several reports described 3D chromatin dynamics properties in the cell developmental context 33,34 , upon loss of cell fate 35,36 , senescence 37,38 or in response to hormonal exposure 39 . Our observations indicate that the capacity of enhancer loop formation is maintained in a highlydifferentiated tissue such as the islets and it is coupled with transcriptional regulatory changes, in response to an external stimulus.The model used in our study to explore chromatin dynamics is of particular interest because it mimics the inflammatory environment that the pancreatic islets may face in the early stages of T1D.…”

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

“…GPRC6A is expressed in 393 pancreatic β-cells and participates in endocrine metabolism 39 and this SNP is linked to a 394 non-functional variant of GPRC6A receptor protein 40 . Furthermore, LMI identified 395 rs17078438 (6q22.1) in RFX6, a pancreas-specific gene involved in endocrine 396 development 41 (Figure 5). 397…”

“…109 (40) University of Texas MD Anderson Cancer Center, Houston, TX, US. 110 (41) Population Health Department, QIMR Berghofer Medical Research 111 Institute, Brisbane, Queensland, Australia. 112 (42) Division of Public Health Sciences, Fred Hutchinson Cancer Research 113 Center, Seattle, WA, US.…”

“…Bioinformatics assessments included evidence of functional impact 66,67 , annotation in 611 overlapping genes and pathways 66 , methylation quantitative trait locus in leukocyte DNA 612 from a subset of the PanGenEU controls (mQTLs), expression QTL (eQTLs) in normal 613 and tumoral pancreas (GTEx and TCGA, respectively) 68,69 , annotation in PC-associated 614 long non-coding RNA (lncRNAs) 19 , protein quantitative trait locus analysis in plasma 615 (pQTLs) 70 , overlap with regulatory chromatin marks in pancreatic tissue obtained from 616 ENCODE 71 , association with relevant human diseases 72 , and annotation in differentially 617 open chromatin regions (DORs) in human pancreatic cells 41 . We also investigated 618 whether prioritized variants had been previously associated with PC comorbidities or 619 other types of cancers 5 .…”