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Expression DATA from E11.5 pancreatic buds treated with I-BET151 or JQ1 for 24h

ABSTRACT: Bromodomain and Extra-terminal (BET) proteins are epigenetic readers that interact with acetylated lysines of histone tails. Recent studies have demonstrated their role in cancer progression, as they recruit key components of the transcriptional machinery to modulate gene expression. However, their role during embryonic development of the pancreas has never been studied. Using mouse embryonic pancreatic explants and human IPSC, we show that inhibition of BET proteins with either I-BET151 or JQ1 dramatically enhances the number of neurogenin3 (NEUROG3) endocrine progenitors, leading to an increased number of endocrine cells in the pancreatic explants. Despite inducing several β cell markers, BETi also strongly down-regulated Ins1 expression in developed explants and adult β cells. However, removal of BETi from explants prior to β cell development, as NEUROG3 expression peaks, further led to enhanced β cell development with higher expression of insulin and maturation markers UCN3 and MAFA. Altogether, these results show that BET proteins play a major role in the pancreas endocrine differentiation. Furthermore, they highlight the potential use of BETi to improve β cell replacement therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE109858 | GEO | 2020/01/01

REPOSITORIES: GEO

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Project description:Atoh8 is a transcription factor of the basic-helix-loop-helix (bHLH) family that is expressed in multiple tissues during embryonic development but whose specific functions remain unknown. The gene encoding Atoh8 is induced by various lineage- determining bHLH transcription factors in cell culture, suggesting a possible common role of this gene in multiple bHLH-driven differentiation programs. In the pancreas, the pro-endocrine bHLH factors Neurogenin3 (Neurog3) and NeuroD1 activate Atoh8 expression. Moreover, Atoh8 is expressed in the embryonic pancreas confirming its participation in the pancreatic transcriptional cascade. This work aims at gaining insight into the molecular function of Atoh8 during the endocrine differentiation program initiated by Neurog3 in the pancreas. To this aim, we have generated a recombinant adenovirus encoding an Atoh8-specific shRNA (Ad-shAtoh8) and used it to down-regulate expression of the Atoh8 gene in Neurog3-expressing pancreatic ductal cells (mPAC), a cellular model of endocrine cell differentiation. Thus, we have compared global changes in gene expression profiles between cells treated with Ad-Neurog3+shControl and cells treated with Ad-Neurog3+shAtoh8 using Affymetrix microarrays. Our results show that Atoh8 silencing significantly affects the expression of 293 genes in Neurog3-expressing mPAC cells. Gene Ontology analysis has revealed cell cycle as the biological function most significantly represented among the modified genes. These results uncover a potential function of Math6 as a regulator of cell cycle progression and provide novel insights into the link between Neurog3 and the regulation of the cell cycle. mPAC cells (mouse pancreatic duct cells) overexpressing Neurogenin3 were divided in 2 groups according to the shRNA encoded by the recombinant adenoviruses used: 1) Scramble shRNA (control for the infection effect), 2) Atonal Homolog 8-specific shRNA. Experiment was performed three independent times (3 independent biological replicates).

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Expression DATA from E11.5 pancreatic buds treated with I-BET151 or JQ1 for 24h

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