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.
Highlights
Cell fate specification during development involves activation and repression of specific generegulatory networks, which are driven by changes in extracellular environment
We predicted that performing a screen for signaling-induced histone modifications in pancreatic progenitors would reveal chromatin modifiers and signaling pathways that modulate beta cell induction, and that pharmacologic or genetic targeting of relevant modifiers could enhance beta cell production
We uncovered a novel function for the chromatin modifier, MSK1/2, in suppressing endocrine and promoting acinar differentiation during pancreatic development
Summary
Cell fate specification during development involves activation and repression of specific generegulatory networks, which are driven by changes in extracellular environment. Dynamics in such networks are mediated by lineage-specific transcription factors that recruit, among other proteins, histone-modifying enzymes to relevant loci [1, 2]. The histonemodifying enzymes are themselves regulated by changes in the extracellular environment, mediating responses to inductive cues [3,4,5,6]. The loss of function or pharmacological inhibition of histone modifying enzymes in the progenitors of various lineages has been shown to modulate their eventual fate choice [7, 8]. We examined histone modifications induced by signaling pathways in the pancreatic beta cell progenitors, focusing on genes that are key drivers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
