C-Myc down-regulation is required for pre-acinar to acinar maturation in the pancreas
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE77411 | GEO | 2017/12/11
SECONDARY ACCESSION(S): PRJNA310233
REPOSITORIES: GEO
Similar Datasets
Project description:Multipotent pancreatic progenitors (MPC) are defined as Ptf1a+, Mychigh, Cpa+ cells. During the transition from MPC to unipotent acinar progenitors, c-Myc is down-regulated whereas Ptf1a is up-regulated, leading to the deployment of the acinar program. Here, we show that c-Myc and Ptf1a interact directly and c-Myc binds to, and represses, the transcriptional activity of the PTF1 complex in vitro and in vivo. Using Ela1-Myc mice, in which c-Myc is overexpressed in acinar cells starting at E14.5, we find that acinar cells fail to undergo normal maturation at P1 and this is followed by a massive subsequent repression of the acinar programme. Lineage tracing with Ptf1aCreERT2;Rosa26YFP and Ela1-Myc;Ptf1aCreERT2;Rosa26YFP mice receiving TMX at E15.5 and analyzed at E18.5 revealed that c-Myc overexpression is associated with activation of a hepatic programme but not with pancreatic lineage misspecification At 8 weeks, the silencing of the acinar program is associated with increased expression of the PRC2 complex in a c-Myc dependent manner. Genome wide studies show that Ptf1a and c-Myc display partially overlapping chromatin occupancy patterns and DNA binding competition. We conclude that c-Myc down-regulation during development is crucial for the maturation of pre-acinar to acinar cells. c-Myc overexpression may contribute to pancreatic carcinogenesis by restraining cell differentiation and rendering cells susceptible to transformation.
2017-12-11 | GSE77410 | GEO
Project description:Multipotent pancreatic progenitors (MPC) are defined as Ptf1a+, Mychigh, Cpa+ cells. During the transition from MPC to unipotent acinar progenitors, c-Myc is down-regulated whereas Ptf1a is up-regulated, leading to the deployment of the acinar program. Here, we show that c-Myc and Ptf1a interact directly and c-Myc binds to, and represses, the transcriptional activity of the PTF1 complex in vitro and in vivo. Using Ela1-Myc mice, in which c-Myc is overexpressed in acinar cells starting at E14.5, we find that acinar cells fail to undergo normal maturation at P1 and this is followed by a massive subsequent repression of the acinar programme. Lineage tracing with Ptf1aCreERT2;Rosa26YFP and Ela1-Myc;Ptf1aCreERT2;Rosa26YFP mice receiving TMX at E15.5 and analyzed at E18.5 revealed that c-Myc overexpression is associated with activation of a hepatic programme but not with pancreatic lineage misspecification At 8 weeks, the silencing of the acinar program is associated with increased expression of the PRC2 complex in a c-Myc dependent manner. Genome wide studies show that Ptf1a and c-Myc display partially overlapping chromatin occupancy patterns and DNA binding competition. We conclude that c-Myc down-regulation during development is crucial for the maturation of pre-acinar to acinar cells. c-Myc overexpression may contribute to pancreatic carcinogenesis by restraining cell differentiation and rendering cells susceptible to transformation.
2017-12-11 | GSE77409 | GEO
Project description:c-Myc down-regulation is required for pre-acinar to acinar maturation in the pancreas
| PRJNA310233 | ENA
Project description:Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G(1) phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G(1)-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.
| S-EPMC3001006 | biostudies-literature
Project description:The final stages of of megakaryocyte (MK) maturation involve a series of steps, including polyploidization and proplatelet formation. Although these processes are highly dependent on dynamic changes in the microtubule (MT) cytoskeleton, the mechanisms responsible for regulation of MTs in MKs remain poorly defined. Stathmin is a highly conserved MT-regulatory protein that has been suggested to play a role in MK differentiation of human leukemic cell lines. However, previous studies defining this relationship have reached contradictory conclusions. In this study, we addressed this controversy and investigated the role of stathmin in primary human MKs. To explore the importance of stathmin down-regulation during megakaryocytopoiesis, we used a lentiviral-mediated gene delivery system to prevent physiologic down-regulation of stathmin in primary MKs. We demonstrated that sustained expression of constitutively active stathmin delayed cytoplasmic maturation (ie, glycoprotein GPIb and platelet factor 4 expression) and reduced the ability of MKs to achieve high levels of ploidy. Moreover, platelet production was impaired in MKs in which down-regulation of stathmin expression was prevented. These studies indicate that suppression of stathmin is biologically important for MK maturation and platelet production and support the importance of MT regulation during the final stages of thrombopoiesis.
| S-EPMC3099574 | biostudies-literature
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2015-05-19 | GSE61638 | GEO
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2016-01-19 | E-GEOD-65546 | biostudies-arrayexpress
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2015-02-03 | E-GEOD-65587 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths worldwide1. Studies in human tissues and in mouse models have suggested that for many cancers, stem cells sustain early mutations driving tumour development2,3. For the pancreas, however, mechanisms underlying cellular renewal and initiation of PDAC remain unresolved. Here, using lineage tracing from the endogenous telomerase reverse transcriptase (Tert) locus, we identify a rare TERT-positive subpopulation of pancreatic acinar cells dispersed throughout the exocrine compartment. During homeostasis, these TERThigh acinar cells renew the pancreas by forming expanding clones of acinar cells, whereas randomly marked acinar cells do not form these clones. Specific expression of mutant Kras in TERThigh acinar cells accelerates acinar clone formation and causes transdifferentiation to ductal pre-invasive pancreatic intraepithelial neoplasms by upregulating Ras-MAPK signalling and activating the downstream kinase ERK (phospho-ERK). In resected human pancreatic neoplasms, we find that foci of phospho-ERK-positive acinar cells are common and frequently contain activating KRAS mutations, suggesting that these acinar regions represent an early cancer precursor lesion. These data support a model in which rare TERThigh acinar cells may sustain KRAS mutations, driving acinar cell expansion and creating a field of aberrant cells initiating pancreatic tumorigenesis.
| S-EPMC9347609 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-10-01 | E-GEOD-61686 | biostudies-arrayexpress