The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development

Neha Bhat, Jeehye Park, Huda Y. Zoghbi, J. Simon C. Arthur, Kenneth S. Zaret (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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Abstract

Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates.
Original languageEnglish
Article numbere0166703
Pages (from-to)1-31
Number of pages31
JournalPLoS ONE
Volume11
Issue number12
DOIs
Publication statusPublished - 14 Dec 2016

Keywords

  • Chromatin
  • Cell differentiation
  • Insulin
  • Multipotency
  • Glucagon
  • Endocrine Cells
  • Histone modification
  • Phosphorylation

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