Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

JCI Insight. 2021 Sep 22;6(18):e151621. doi: 10.1172/jci.insight.151621.


Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

Keywords: Beta cells; Bioinformatics; Cell Biology; Diabetes; Endocrinology.

Publication types

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

MeSH terms

  • Adult
  • Electrophysiological Phenomena
  • Gene Expression
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Maf Transcription Factors, Large / genetics
  • Maf Transcription Factors, Large / metabolism
  • MafB Transcription Factor / genetics
  • MafB Transcription Factor / metabolism
  • Middle Aged
  • Sequence Analysis, RNA
  • Single-Cell Analysis
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Transcriptome
  • Young Adult


  • ARX protein, human
  • Homeodomain Proteins
  • Insulin
  • MAFA protein, human
  • MAFB protein, human
  • Maf Transcription Factors, Large
  • MafB Transcription Factor
  • Transcription Factors