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Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE86263 | GEO | 2016/09/01

SECONDARY ACCESSION(S): PRJNA341322

REPOSITORIES: GEO

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Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A.

Project description:Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.

| S-EPMC5126291 | biostudies-literature

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A [ChIP-Seq]

Project description:Genome-wide maps of Ptf1a-bound sites in adult pancrea acinar cells.

2016-09-01 | GSE86262 | GEO

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A [E18.5 RNA-Seq]

Project description:RNA-seq analysis of RNA from embryonic day 18.5 pancreas

2016-09-09 | GSE86568 | GEO

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A [6-day RNA-Seq]

Project description:RNA-seq analysis documented mRNA changes in total pancreatic RNA preparations 6 days after Ptf1a inactivation.

2016-09-01 | GSE86261 | GEO

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A

Project description:Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A

| PRJNA341322 | ENA

The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.

Project description:Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

| S-EPMC4536747 | biostudies-literature

Dicer is required for maintenance of adult pancreatic acinar cell identity and plays a role in Kras-driven pancreatic neoplasia.

Project description:The role of miRNA processing in the maintenance of adult pancreatic acinar cell identity and during the initiation and progression of pancreatic neoplasia has not been studied in detail. In this work, we deleted Dicer specifically in adult pancreatic acinar cells, with or without simultaneous activation of oncogenic Kras. We found that Dicer is essential for the maintenance of acinar cell identity. Acinar cells lacking Dicer showed increased plasticity, as evidenced by loss of polarity, initiation of epithelial-to-mesenchymal transition (EMT) and acinar-to-ductal metaplasia (ADM). In the context of oncogenic Kras activation, the initiation of ADM and pancreatic intraepithelial neoplasia (PanIN) were both highly sensitive to Dicer gene dosage. Homozygous Dicer deletion accelerated the formation of ADM but not PanIN. In contrast, heterozygous Dicer deletion accelerated PanIN initiation, revealing complex roles for Dicer in the regulation of both normal and neoplastic pancreatic epithelial identity.

| S-EPMC4236134 | biostudies-literature

Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood.

Project description:The basic helix-loop-helix (bHLH) transcription factor PTF1a is critical to the development of the embryonic pancreas. It is required early for the formation of the undifferentiated tubular epithelium of the nascent pancreatic rudiment and then becomes restricted to the differentiating acinar cells, where it directs the transcriptional activation of the secretory digestive enzyme genes. Here we report that the complex temporal and spatial expression of Ptf1a is controlled by at least three separable gene-flanking regions. A 14.8-kb control domain immediately downstream of the last Ptf1a exon is highly conserved among mammals and directs expression in the dorsal part of the spinal cord but has very little activity in the embryonic or neonatal pancreas. A 13.4-kb proximal promoter domain initiates limited expression in cells that begin the acinar differentiation program. The activity of the proximal promoter domain is complemented by an adjacent 2.3-kb autoregulatory enhancer that is able to activate a heterologous minimal promoter with high-level penetrance in the pancreases of transgenic mice. During embryonic development, the enhancer initiates expression in the early precursor epithelium and then superinduces expression in acinar cells at the onset of their development. The enhancer contains two evolutionarily conserved binding sites for the active form of PTF1a, a trimeric complex composed of PTF1a, one of the common bHLH E proteins, and either RBPJ or RBPJL. The two sites are essential for acinar cell-specific transcription in transfected cell lines and mice. In mature acinar cells, the enhancer and PTF1a establish an autoregulatory loop that reinforces and maintains Ptf1a expression. Indeed, the trimeric PTF1 complex forms dual autoregulatory loops with the Ptf1a and Rbpjl genes that may maintain the stable phenotype of pancreatic acinar cells.

| S-EPMC2519732 | biostudies-literature

Expression in parotid acinar cells during terminal differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-02-03 | E-GEOD-65587 | biostudies-arrayexpress

Ptf1a inactivation in adult pancreatic acinar cells causes apoptosis through activation of the endoplasmic reticulum stress pathway.

Project description:Pancreas transcription factor 1 subunit alpha (PTF1A) is one of the key regulators in pancreatogenesis. In adults, it transcribes digestive enzymes, but its other functions remain largely unknown. Recent conditional knockout studies using Ptf1aCreER/floxed heterozygous mouse models have found PTF1A contributes to the identity maintenance of acinar cells and prevents tumorigenesis caused by the oncogenic gene Kras. However, Ptf1a heterozygote is known to behave differently from homozygote. To elucidate the effects of Ptf1a homozygous loss, we prepared Elastase-CreERTM; Ptf1afloxed/floxed mice and found that homozygous Ptf1a deletion in adult acinar cells causes severe apoptosis. Electron microscopy revealed endoplasmic reticulum (ER) stress, a known cause of unfolded protein responses (UPR). We confirmed that UPR was upregulated by the activating transcription factor 6 (ATF6) and protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) pathways, but not the inositol requiring enzyme 1 (IRE1) pathway. Furthermore, we detected the expression of CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP), a pro-apoptotic factor, indicating the apoptosis was induced through UPR. Our homozygous model helps clarify the role PTF1A has on the homeostasis and pathogenesis of exocrine pancreas in mice.

| S-EPMC6202406 | biostudies-literature

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