MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86290 | GEO | 2016/09/01
SECONDARY ACCESSION(S): PRJNA341364
REPOSITORIES: GEO
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Project description:Much remains unknown regarding the regulatory networks formed by transcription factors in mature, differentiated mammalian cells in vivo, despite many studies of individual DNA-binding transcription factors. We report a constellation of feed-forward loops formed by the pancreatic transcription factors MIST1 and PTF1 that govern the differentiated phenotype of the adult pancreatic acinar cell. PTF1 is an atypical basic helix-loop-helix transcription factor complex of pancreatic acinar cells and is critical to acinar cell fate specification and differentiation. MIST1, also a basic helix-loop-helix transcription factor, enhances the formation and maintenance of the specialized phenotype of professional secretory cells. The MIST1 and PTF1 collaboration controls a wide range of specialized cellular processes, including secretory protein synthesis and processing, exocytosis, and homeostasis of the endoplasmic reticulum. PTF1 drives Mist1 transcription, and MIST1 and PTF1 bind and drive the transcription of over 100 downstream acinar genes. PTF1 binds two canonical bipartite sites within a 0.7-kb transcriptional enhancer upstream of Mist1 that are essential for the activity of the enhancer in vivo MIST1 and PTF1 coregulate target genes synergistically or additively, depending on the target transcriptional enhancer. The frequent close binding proximity of PTF1 and MIST1 in pancreatic acinar cell chromatin implies extensive collaboration although the collaboration is not dependent on a stable physical interaction.
| S-EPMC5108882 | biostudies-literature
Project description:MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
2016-09-01 | GSE86289 | GEO
Project description:MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
2016-09-01 | GSE86288 | GEO
Project description:MIST1 and PTF1 Collaborate in Feed-forward Regulatory Loops that Maintain the Pancreatic Acinar Phenotype in Adult Mice
| PRJNA341364 | ENA
Project description:Background & aimsEarly embryogenesis involves cell fate decisions that define the body axes and establish pools of progenitor cells. Development does not stop once lineages are specified; cells continue to undergo specific maturation events, and changes in gene expression patterns lead to their unique physiological functions. Secretory pancreatic acinar cells mature postnatally to synthesize large amounts of protein, polarize, and communicate with other cells. The transcription factor MIST1 is expressed by only secretory cells and regulates maturation events. MIST1-deficient acinar cells in mice do not establish apical-basal polarity, properly position zymogen granules, or communicate with adjacent cells, disrupting pancreatic function. We investigated whether MIST1 directly induces and maintains the mature phenotype of acinar cells.MethodsWe analyzed the effects of Cre-mediated expression of Mist1 in adult Mist1-deficient (Mist1(KO)) mice. Pancreatic tissues were collected and analyzed by light and electron microscopy, immunohistochemistry, real-time polymerase chain reaction analysis, and chromatin immunoprecipitation. Primary acini were isolated from mice and analyzed in amylase secretion assays.ResultsInduced expression of Mist1 in adult Mist1(KO) mice restored wild-type gene expression patterns in acinar cells. The acinar cells changed phenotypes, establishing apical-basal polarity, increasing the size of zymogen granules, reorganizing the cytoskeletal network, communicating intercellularly (by synthesizing gap junctions), and undergoing exocytosis.ConclusionsThe exocrine pancreas of adult mice can be remodeled by re-expression of the transcription factor MIST1. MIST1 regulates acinar cell maturation and might be used to repair damaged pancreata in patients with pancreatic disorders.
| S-EPMC3664941 | biostudies-literature
Project description:Background & aimsMist1 is a basic helix-loop-helix (bHLH) transcription factor that is important to the proper development of the exocrine pancreas. The aim of this study was to investigate the role of Mist1 in modulating acinar cell proliferation.MethodsDuctal and acinar pancreatic cell lines were engineered to express an inducible Mist1 complementary DNA or to express a short hairpin RNA that targeted endogenous Mist1. Alterations in RNA and protein levels were detected by real-time reverse-transcription polymerase chain reaction and immunoblots. Chromatin immunoprecipitation and reporter gene assays were performed to map Mist1-responsive elements on target genes; the overall proliferation index of acinar cells from Mist1 null pancreata was evaluated by immunohistochemistry.ResultsExpression of Mist1 resulted in a significant decrease in the proliferative potential of cells that was associated with induced expression of p21(CIP1/WAF1). Short hairpin RNA-directed knockdown of p21(CIP1/WAF1) generated cells that were refractory to Mist1 expression, whereas knockdown of Mist1 transcripts or deletion of Mist1 from the mouse genome led to increased cell proliferation and a concomitant decrease in p21(CIP1/WAF1) protein levels. Surprisingly, Mist1-dependent activation of the p21(CIP1/WAF1) promoter was independent of classic basic helix-loop-helix protein binding sites. Instead, Sp1 binding sites were essential for Mist1-dependent transcription, suggesting that Mist1 activates p21(CIP1/WAF1) expression through a unique Sp1 pathway. Indeed, coimmunoprecipitation studies demonstrated that Mist1 and Sp1 were found within the same transcription complex.ConclusionsOur results show that Mist1 has a dual role in the development of the exocrine pancreas: controlling cell proliferation and promoting terminal differentiation.
| S-EPMC2853247 | biostudies-literature
Project description:Feed-forward loops (FFLs) are among the most ubiquitously found motifs of reaction networks in nature. However, little is known about their stochastic behavior and the variety of network phenotypes they can exhibit. In this study, we provide full characterizations of the properties of stochastic multimodality of FFLs, and how switching between different network phenotypes are controlled. We have computed the exact steady-state probability landscapes of all eight types of coherent and incoherent FFLs using the finite-butter Accurate Chemical Master Equation (ACME) algorithm, and quantified the exact topological features of their high-dimensional probability landscapes using persistent homology. Through analysis of the degree of multimodality for each of a set of 10,812 probability landscapes, where each landscape resides over 105-106 microstates, we have constructed comprehensive phase diagrams of all relevant behavior of FFL multimodality over broad ranges of input and regulation intensities, as well as different regimes of promoter binding dynamics. In addition, we have quantified the topological sensitivity of the multimodality of the landscapes to regulation intensities. Our results show that with slow binding and unbinding dynamics of transcription factor to promoter, FFLs exhibit strong stochastic behavior that is very different from what would be inferred from deterministic models. In addition, input intensity play major roles in the phenotypes of FFLs: At weak input intensity, FFL exhibit monomodality, but strong input intensity may result in up to 6 stable phenotypes. Furthermore, we found that gene duplication can enlarge stable regions of specific multimodalities and enrich the phenotypic diversity of FFL networks, providing means for cells toward better adaptation to changing environment. Our results are directly applicable to analysis of behavior of FFLs in biological processes such as stem cell differentiation and for design of synthetic networks when certain phenotypic behavior is desired.
| S-EPMC8297706 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis is a progressive scarring disease characterized by extracellular matrix accumulation and altered mechanical properties of lung tissue. Recent studies support the hypothesis that these compositional and mechanical changes create a progressive feed-forward loop in which enhanced matrix deposition and tissue stiffening contribute to fibroblast and myofibroblast differentiation and activation, which further perpetuates matrix production and stiffening. The biomechanical properties of tissues are sensed and responded to by mechanotransduction pathways that facilitate sensing of changes in mechanical cues by tissue resident cells and convert the mechanical signals into downstream biochemical signals. Although our understanding of mechanotransduction pathways associated with pulmonary fibrosis remains incomplete, recent progress has allowed us to begin to elucidate the specific mechanisms supporting fibrotic feed-forward loops. The mechanosensors discussed here include integrins, Piezo channels, transient receptor potential channels, and nonselective ion channels. Also discussed are downstream transcription factors, including myocardin-related transcription factor and Yes-associated protein/transcriptional coactivator with PDZ-binding motif. This review describes mechanosensors and mechanotransduction pathways associated with fibrosis progression and highlights promising therapeutic insights.
| S-EPMC7768346 | biostudies-literature
Project description:Feed-forward loops (FFLs) represent an important and basic network motif to understand specific biological functions. Cyclic-AMP (cAMP) receptor protein (CRP), a transcription factor (TF), mediates catabolite repression and regulates more than 400 genes in response to changes in intracellular concentrations of cAMP in Escherichia coli. CRP participates in some FFLs, such as araBAD and araFGH operons and adapts to fluctuating environmental nutrients, thereby enhancing the survivability of E. coli. Although computational simulations have been conducted to explore the potential functionality of FFLs, a comprehensive study on the functions of all structural types on the basis of in vivo data is lacking. Moreover, the regulatory role of CRP-mediated FFLs (CRP-FFLs) remains obscure. We identified 393 CRP-FFLs in E. coli using EcoCyc and RegulonDB. Dose?response genomic microarray of E. coli revealed dynamic gene expression of each target gene of CRP-FFLs in response to a range of cAMP dosages. All eight types of FFLs were present in CRP regulon with various expression patterns of each CRP-FFL, which were further divided into five functional groups. The microarray and reported regulatory relationships identified 202 CRP-FFLs that were directly regulated by CRP in these eight types of FFLs. Interestingly, 34% (147/432) of genes were directly regulated by CRP and CRP-regulated TFs, which indicates that these CRP-regulated genes were also regulated by other CRP-regulated TFs responding to environmental signals through CRP-FFLs. Furthermore, we applied gene ontology annotation to reveal the biological functions of CRP-FFLs.
| S-EPMC6121374 | biostudies-literature
Project description:BACKGROUND & AIMS:Invasive pancreatic ductal adenocarcinoma is thought to originate from duct-like lesions called pancreatic intraepithelial neoplasia (PanIN). PanINs progress from low grade (PanIN-1) to high grade (PanIN-3) as the cells attain molecular alterations to key regulatory genes, including activating mutations in the KRAS protooncogene. Despite a well-documented progression model, our knowledge of the initiator cells of PanINs and the transcriptional networks and signaling pathways that impact PanIN formation remains incomplete. METHODS:In this study, we examined the importance of the acinar-restricted transcription factor Mist1 to KrasG12D-induced mouse PanIN (mPanIN) formation in 3 different mouse models of pancreatic cancer. RESULTS:In the absence of Mist1 (Mist1KO), KrasG12D-expressing mice exhibited severe exocrine pancreatic defects that were rescued by ectopic expression of Mist1 in acinar cells. mPanIN development was greatly accelerated in Mist1KO/KrasG12D/+ pancreata, and in vitro assays revealed that Mist1KO acinar cells were predisposed to convert to a ductal phenotype and activate epidermal growth factor receptor (EGFR) and Notch-signaling pathways. CONCLUSIONS:We propose that convergence of EGFR, Notch, and Kras pathways in acinar cells lacking Mist1 leads to enhanced mPanIN formation.
| S-EPMC2845927 | biostudies-literature