PloS one, 2016-12, Vol.11 (12), p.e0166703-e0166703
2016
Details
- Autor(en) / Beteiligte
- Titel
- The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development
- Ist Teil von
- PloS one, 2016-12, Vol.11 (12), p.e0166703-e0166703
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0166703Titel-ID: cdi_plos_journals_1848850649
- Format
- –
- Schlagworte
- Alleles, Animals, Apoptosis, Beta cells, Biology and Life Sciences, Bridged Bicyclo Compounds, Heterocyclic - chemistry, Cell Differentiation, Cell Lineage, Cell Proliferation, Cellular signal transduction, Chromatin, Chromatin - chemistry, Developmental biology, Diabetes mellitus, DNA methylation, Embryos, Endocrine System, Enzymes, Explants, Female, Fluorescent antibody technique, Gene Expression Profiling, Genes, Histone H3, Histones - chemistry, Immunofluorescence, Insulin, Insulin-Secreting Cells - cytology, Isoforms, Kinases, Male, Medicine, Medicine and Health Sciences, Mice, Mice, Inbred C3H, Mice, Knockout, Morphogenesis, Oxadiazoles - chemistry, Pancreas, Pancreas - embryology, Pancreatic beta cells, Pharmacology, Phosphorylation, Promoter Regions, Genetic, Proteins, Ribosomal Protein S6 Kinases, 90-kDa - metabolism, Rodents, Signal Transduction, Stem cells, Transcription factors, Transduction