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Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells

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

ORGANISM(S): Homo sapiens

PROVIDER: GSE120017 | GEO | 2019/09/17

REPOSITORIES: GEO

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Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ATAC-seq]

Project description:Abnormal differentiation contributes to the spectrum of aberrant properties of tumor cells. Differentiation of both normal and tumor cells is controlled by regulatory networks enforced by transcription factors (TFs) involved in lineage specification. Among them, pioneer factors such as FOXA1/2, are able to bind and make accessible naïve chromatin, thus critically contributing to the establishment of gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by massive heterogeneity, with the coexistence at all disease stages of well- and poorly-differentiated cells with diverging transcriptional networks. We found that FOXA2, a TF controlling pancreas specification, was expressed in both well- and poorly-differentiated PDAC cells, but it controlled distinct gene expression programs and displayed extensively different genomic distributions because of its partnership with TFs expressed in a differentiation grade-specific manner, such as HNF1 and HOXB8/9 in well- and poorly-differentiated cells, respectively. These data suggest that pioneer TFs such as FOXA2 are versatile transcriptional regulators whose broad contribution to the gene regulatory networks of highly heterogeneous cancers such as PDACs, depends on the differential availability of partner TFs expressed in distinct tumor cells.

2019-09-17 | GSE128100 | GEO

Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [RNA-seq]

2019-09-17 | GSE119931 | GEO

Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ChIP-seq]

2019-09-17 | GSE119930 | GEO

FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner.

Project description:Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.

| S-EPMC6792020 | biostudies-literature

Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells

Project description:Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells

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Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [RNA-seq]

Project description:Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [RNA-seq]

| PRJNA490732 | ENA

Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ChIP-seq]

Project description:Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ChIP-seq]

| PRJNA490733 | ENA

Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ATAC-seq]

Project description:Cell differentiation grade determines distinct FOXA2 contributions to the cis-regulatory networks of pancreatic cancer cells [ATAC-seq]

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Brachyury, Foxa2 and the cis-Regulatory Origins of the Notochord.

Project description:A main challenge of modern biology is to understand how specific constellations of genes are activated to differentiate cells and give rise to distinct tissues. This study focuses on elucidating how gene expression is initiated in the notochord, an axial structure that provides support and patterning signals to embryos of humans and all other chordates. Although numerous notochord genes have been identified, the regulatory DNAs that orchestrate development and propel evolution of this structure by eliciting notochord gene expression remain mostly uncharted, and the information on their configuration and recurrence is still quite fragmentary. Here we used the simple chordate Ciona for a systematic analysis of notochord cis-regulatory modules (CRMs), and investigated their composition, architectural constraints, predictive ability and evolutionary conservation. We found that most Ciona notochord CRMs relied upon variable combinations of binding sites for the transcription factors Brachyury and/or Foxa2, which can act either synergistically or independently from one another. Notably, one of these CRMs contains a Brachyury binding site juxtaposed to an (AC) microsatellite, an unusual arrangement also found in Brachyury-bound regulatory regions in mouse. In contrast, different subsets of CRMs relied upon binding sites for transcription factors of widely diverse families. Surprisingly, we found that neither intra-genomic nor interspecific conservation of binding sites were reliably predictive hallmarks of notochord CRMs. We propose that rather than obeying a rigid sequence-based cis-regulatory code, most notochord CRMs are rather unique. Yet, this study uncovered essential elements recurrently used by divergent chordates as basic building blocks for notochord CRMs.

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FOXA2 Is Required for Enhancer Priming during Pancreatic Differentiation.

Project description:Transcriptional regulatory mechanisms of lineage priming in embryonic development are largely uncharacterized because of the difficulty of isolating transient progenitor populations. Directed differentiation of human pluripotent stem cells (hPSCs) combined with gene editing provides a powerful system to define precise temporal gene requirements for progressive chromatin changes during cell fate transitions. Here, we map the dynamic chromatin landscape associated with sequential stages of pancreatic differentiation from hPSCs. Our analysis of chromatin accessibility dynamics led us to uncover a requirement for FOXA2, known as a pioneer factor, in human pancreas specification not previously shown from mouse knockout studies. FOXA2 knockout hPSCs formed reduced numbers of pancreatic progenitors accompanied by impaired recruitment of GATA6 to pancreatic enhancers. Furthermore, FOXA2 is required for proper chromatin remodeling and H3K4me1 deposition during enhancer priming. This work highlights the power of combining hPSC differentiation, genome editing, and computational genomics for discovering transcriptional mechanisms during development.

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