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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

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

PROVIDER: PRJNA634348 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11826626.fastq.gz	Fastqsanger.gz
	SRR11826627.fastq.gz	Fastqsanger.gz
	SRR11826628.fastq.gz	Fastqsanger.gz
	SRR11826629.fastq.gz	Fastqsanger.gz
	SRR11826630.fastq.gz	Fastqsanger.gz

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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

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: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]

| PRJNA634353 | 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, NKX2-1, and PROX1 co-regulate subtype-specific genes in small-cell lung cancer.

Project description:Lineage-defining transcription factors (LTFs) play key roles in small-cell lung cancer (SCLC) pathophysiology. Delineating the LTF-regulated genes operative in SCLC could provide a road map to identify SCLC dependencies. We integrated chromatin landscape and transcriptome analyses of patient-derived SCLC preclinical models to identify super-enhancers (SEs) and their associated genes in the ASCL1-, NEUROD1-, and POU2F3-high SCLC subtypes. We find SE signatures predict LTF-based classification of SCLC, and the SE-associated genes are enriched with those defined as common essential genes in DepMap. In addition, in ASCL1-high SCLC, we show ASCL1 complexes with NKX2-1 and PROX1 to co-regulate genes functioning in NOTCH signaling, catecholamine biosynthesis, and cell-cycle processes. Depletion of ASCL1 demonstrates it is a key dependency factor in preclinical SCLC models and directly regulates multiple DepMap-defined essential genes. We provide LTF/SE-based subtype-specific gene sets for SCLC for further therapeutic investigation.

| S-EPMC8384902 | biostudies-literature

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

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:This SuperSeries is composed of the SubSeries listed below.

2021-05-01 | GSE151002 | GEO

FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [RNA-seq]

Project description:In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1’s influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1’s cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed in ASCL1-driven NEPC. FOXA2 and ASCL1 interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer.

2024-10-23 | GSE273957 | GEO

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