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Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [HiCHIP]

ABSTRACT: Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [HiCHIP]

PROVIDER: PRJNA634353 | ENA |

REPOSITORIES: ENA

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Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [HiCHIP]

Project description:Heterogeneity between tumors is a major barrier to the treatment of small cell lung cancer (SCLC). Identification of molecular markers to characterize and classify tumors can facilitate the diagnosis and development of targeted therapies. Here, we analyzed genomic regions, called super enhancers (SE), across multiple SCLC cell lines and patient-derived xenograft models, and find SE enrichment is sufficient to classify SCLC models into recently defined SCLC molecular subtypes SCLC-A, SCLC-N, and SCLC-P defined by the transcription factors ASCL1, NEUROD1, and POU2F3, respectively. 3D chromatin structure analysis identified genes associated with the SE that assemble into subtype-specific tumor-signatures with genes functioning in diverse processes. Focusing on the SCLC-A subtype, transcription factors NKX2-1 and PROX1 were identified as ASCL1-interacting proteins. All three factors bind overlapping genomic regions within SEs in SCLC-A cell line models. Nevertheless, combined loss of all three factors suppresses growth of SCLC-A similar to that seen with ASCL1 loss alone, continuing to place ASCL1 as a key dependency factor in a subset of SCLC. Focusing on genes co-regulated by the three transcription factors, two SCLC-A subtype-specific cell surface proteins, SCN3A and KCNB2, were identified. Loss of either channel alone did not disrupt SCLC-A growth in vitro, but they may serve as diagnostic tools in subtyping SCLC.

2021-05-01 | GSE151001 | GEO

Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [RNA-seq]

2021-05-01 | GSE151000 | GEO

Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [ChIP-seq]

2021-05-01 | GSE150999 | GEO

H3K27ac HiChIP analysis in GI-MEN DOX-ASCL1 cells

Project description:H3K27ac HiChIP analysis was performed in GI-MEN DOX-ASCL1 cells to analyze active chromatin-chromatin interactions in GI-MEN DOX-ASCL1 cells.

2023-11-21 | GSE214792 | GEO

ASCL1, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer.

Project description: Not available

| S-EPMC8384902 | biostudies-literature

Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer

Project description:Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer

| PRJNA634348 | ENA

Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [ChIP-seq]

Project description:Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [ChIP-seq]

| PRJNA634351 | ENA

Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [RNA-seq]

Project description:Lineage transcription factors ASCL1, NKX2-1, and PROX1 are enriched at super enhancers and co-regulate subtype-specific genes in small cell lung cancer [RNA-seq]

| PRJNA634352 | ENA

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

2023-12-08 | PXD037670 | Pride

TTF-1/NKX2-1 and ASCL1 binding regions in NCI-H209 and NKX2-1 binding regions in NCI-H441, replicate 2

Project description:Although Thyroid transcription factor-1 (TTF-1, encoded by NKX2-1 gene) is highly expressed in small cell lung carcinoma (SCLC) and lung adenocarcinoma (LADC), difference in the functional roles of TTF-1 between SCLC and LADC remains to be elucidated. The aim of this study was to clarify the differences in the TTF-1 binding regions and functional roles in SCLC and LADC. Employing chromatin immunoprecipitation-sequencing (ChIP-seq) , here we compared the genome-wide TTF-1-binding profiles and the TTF-1-mediated transcriptional programs in a SCLC and a LADC cell lines. We also investigated ASCL1 binding regions in SCLC cells.

2019-11-30 | GSE139868 | GEO

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