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

Cell Syst. 2018 Sep 26;7(3):310-322.e4. doi: 10.1016/j.cels.2018.07.007. Epub 2018 Aug 22.


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.

Keywords: ATAC-seq; cell lineage; chromatin; development; diabetes; enhancer; genomics; histone modification; islet; pancreas.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cell Lineage
  • Cell Plasticity
  • Cells, Cultured
  • Chromatin / physiology*
  • Chromatin Assembly and Disassembly
  • Diabetes Mellitus / genetics*
  • Diabetes Mellitus / pathology
  • Gene Expression Regulation
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin-Secreting Cells / physiology*
  • Organ Specificity
  • Pancreas / pathology
  • Pancreas / physiology*
  • Pancreas, Exocrine / pathology*
  • Polymorphism, Single Nucleotide
  • Regeneration
  • Risk


  • Chromatin
  • Homeodomain Proteins