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POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer [ChIP-seq]

ABSTRACT: POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer [ChIP-seq]

PROVIDER: PRJNA473830 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7236730.fastq.gz	Fastqsanger.gz
	SRR7236740.fastq.gz	Fastqsanger.gz
	SRR7236750.fastq.gz	Fastqsanger.gz
	SRR7236760.fastq.gz	Fastqsanger.gz
	SRR7236770.fastq.gz	Fastqsanger.gz

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POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer

Project description:POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer

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OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

Project description:ChIP-Seq of C11orf53(OCA-T), COLCA2 and POU2F3(OCT11) in tuft cell lung cancer cell lines. Gene expression changes upon CRISPR knockout of different genes in tuft cell lung cancer cell lines and upon over-expression of C11orf53/POU2F3 alone or in combo in YT330 (a murine Notch high small cell lung cancer cell line)

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POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.

Project description:Small cell lung cancer (SCLC) is widely considered to be a tumor of pulmonary neuroendocrine cells; however, a variant form of this disease has been described that lacks neuroendocrine features. Here, we applied domain-focused CRISPR screening to human cancer cell lines to identify the transcription factor (TF) POU2F3 (POU class 2 homeobox 3; also known as SKN-1a/OCT-11) as a powerful dependency in a subset of SCLC lines. An analysis of human SCLC specimens revealed that POU2F3 is expressed exclusively in variant SCLC tumors that lack expression of neuroendocrine markers and instead express markers of a chemosensory lineage known as tuft cells. Using chromatin- and RNA-profiling experiments, we provide evidence that POU2F3 is a master regulator of tuft cell identity in a variant form of SCLC. Moreover, we show that most SCLC tumors can be classified into one of three lineages based on the expression of POU2F3, ASCL1, or NEUROD1. Our CRISPR screens exposed other unique dependencies in POU2F3-expressing SCLC lines, including the lineage TFs SOX9 and ASCL2 and the receptor tyrosine kinase IGF1R (insulin-like growth factor 1 receptor). These data reveal POU2F3 as a cell identity determinant and a dependency in a tuft cell-like variant of SCLC, which may reflect a previously unrecognized cell of origin or a trans-differentiation event in this disease.

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POU2AF2/C11orf53 functions as a co-activator of POU2F3 by maintaining chromatin accessibility and enhancer activity

Project description:Small cell lung cancer (SCLC), accounting for around 15% of all lung cancers, often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. The POU class 2 homeobox 3 (POU2F3) is a master regulator of tuft cell identity and defines a subtype of SCLC tumors (SCLC-P subtype) that lack the expression of neuroendocrine markers. Here, we have identified a previously uncharacterized protein C11orf53, which is co-expressed with POU2F3 in both SCLC cell lines and patient samples, and defines the same SCLC subtype. C11orf53 is an essential gene for SCLC-P subtype cells’ survival based on genome wide CRISPR screen, and genetic depletion of C11orf53 or POU2F3 induces apoptosis in different SCLC-P subtype cell lines. Furthermore, our biochemical and genome-wide studies have demonstrated that C11orf53 is a novel chromatin-bound protein that occupies broad active enhancer domains and regulates gene expression at active enhancers. Mechanistically, C11orf53 directly interacts with POU2F3 at the POUs domain, and is recruited to chromatin by POU2F3. Depletion of C11orf53 dramatically reduced enhancer H3K27ac levels and chromatin accessibility, resulting a reduction of the expression of POU2F3-dependent tuft cell markers. Based on the expression pattern and molecular function, we have renamed C11orf53 as "POU Class 2 Homeobox Associating Factor 2" (POU2AF2). In summary, our study has identified a new co-activator of POU2 family transcription factors, and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.

2022-09-28 | GSE197426 | GEO

POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer

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2018-06-22 | GSE115124 | GEO

OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

Project description:OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

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