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PAX9 determines epigenetic state transition and cell fate in small cell lung cancer

ABSTRACT: PAX9 determines epigenetic state transition and cell fate in small cell lung cancer

PROVIDER: PRJNA689624 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13355162.fastq.gz	Fastqsanger.gz
	SRR13355163.fastq.gz	Fastqsanger.gz
	SRR13355164_1.fastq.gz	Fastqsanger.gz
	SRR13355164_2.fastq.gz	Fastqsanger.gz
	SRR13355165.fastq.gz	Fastqsanger.gz

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PAX9 determines epigenetic state transition and cell fate in small cell lung cancer

Project description:Small cell lung cancer (SCLC) is a more aggressive and deadlier form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen, we have identified the Paired box protein 9 (PAX9) as an essential factor for the cell viability of SCLC-A type, which accounts for approximately 70% of all SCLC. PAX9 is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis and is overexpressed in human malignant SCLC tumor samples. Genome-wide studies have revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. Genetic depletion of PAX9 leads to a dramatic induction of a primed-active enhancer transition, resulting in an increased expression of a large number of neural differentiation and tumor-suppressive genes in multiple SCLC cell lines. Mechanistically, PAX9 interacts and co-functions with the Nucleosome Remodeling and Deacetylase (NuRD) complex at enhancers and they repress the nearby gene expression, which could be rescued by pharmacological HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that re-activation of the primed enhancers may have therapeutic efficacy in treating SCLC-A type cancers expressing high levels of PAX9.

2021-08-03 | GSE164247 | GEO

PAX9 Determines Epigenetic State Transition and Cell Fate in Cancer.

Project description:Abnormalities in genetic and epigenetic modifications can lead to drastic changes in gene expression profiles that are associated with various cancer types. Small cell lung cancer (SCLC) is an aggressive and deadly form of lung cancer with limited effective therapies currently available. By utilizing a genome-wide CRISPR-Cas9 dropout screen in SCLC cells, we identified paired box protein 9 (PAX9) as an essential factor that is overexpressed in human malignant SCLC tumor samples and is transcriptionally driven by the BAP1/ASXL3/BRD4 epigenetic axis. Genome-wide studies revealed that PAX9 occupies distal enhancer elements and represses gene expression by restricting enhancer activity. In multiple SCLC cell lines, genetic depletion of PAX9 led to significant induction of a primed-active enhancer transition, resulting in increased expression of a large number of neural differentiation and tumor-suppressive genes. Mechanistically, PAX9 interacted and cofunctioned with the nucleosome remodeling and deacetylase (NuRD) complex at enhancers to repress nearby gene expression, which was reversed by pharmacologic HDAC inhibition. Overall, this study provides mechanistic insight into the oncogenic function of the PAX9/NuRD complex epigenetic axis in human SCLC and suggests that reactivation of primed enhancers may have potential therapeutic efficacy in treating SCLC expressing high levels of PAX9. SIGNIFICANCE: A genome-wide screen in small cell lung cancer reveals PAX9/NuRD-mediated epigenetic enhancer silencing and tumor progression, supporting the development of novel personalized therapeutic approaches targeting the PAX9-regulated network.

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Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

Project description:Endothelial Cell Cycle State Determines Propensity for Arterial-Venous Fate

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TCF1 dosage determines cell fate during T cell development.

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TCF1 dosage determines cell fate during T cell development

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TCF1 dosage determines cell fate during T cell development. [scRNA-Seq]

Project description:TCF1 dosage determines cell fate during T cell development. [scRNA-Seq]

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TCF1 dosage determines cell fate during T cell development. [scATAC-Seq]

Project description:TCF1 dosage determines cell fate during T cell development. [scATAC-Seq]

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BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

Project description:BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

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BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

Project description:BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state

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A Developmental Genomic Analysis of Pax1 and Pax9 in Embryonic Intervertebral Disc Development

Project description:Pax1 and Pax9 play redundant, synergistic functions in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. Gene expression profiling of an enriched population of Pax1/Pax9-expressing cells of the embryonic IVD revealed that Pax1 and Pax9 regulate cell proliferation, cartilage development, collagen fibrillogenesis and other processes vital in early IVD morphogenesis. Twenty-nine of the Pax1/Pax9 targets are also associated with axial skeletal defects that phenocopy Pax1/Pax9-deficient mice. Pax1 likely auto-regulates itself and is up-regulated in the absence of Pax9, clarifying how it compensates for the loss of Pax9, while Pax9 is unaffected by the loss of Pax1. Pax1 and Pax9 positively regulate several of the cartilage development genes known to be regulated by the “Sox trio” (Sox5/Sox6/Sox9).

2017-08-25 | GSE63017 | GEO

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