title: The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development.
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.
authors.affiliation: Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Civic Center Blvd., Philadelphia, PA, United States of America.
authors.forename: Neha
authors.initials: N
authors.lastname: Bhat
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, United States of America.
authors.forename: Jeehye
authors.initials: J
authors.lastname: Park
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Baylor College of Medicine, and Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, United States of America.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.affiliation: Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.affiliation: Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Civic Center Blvd., Philadelphia, PA, United States of America.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Zaret
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002843:Chromatin / Q000737:chemistry; D004703:Endocrine System; D005260:Female; D020869:Gene Expression Profiling; D006657:Histones / Q000737:chemistry; D050417:Insulin-Secreting Cells / Q000166:cytology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000737:chemistry; D010179:Pancreas / Q000196:embryology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002843:Chromatin; D006657:Histones; D010069:Oxadiazoles; C570041:SB 747651A; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1