Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

ABSTRACT: Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The purpose of this part of the study was to investigate what genes are affected by BET inhibitor JQ1 in small cell lung cancer cell line COR-L279 (a SCLC-N subtype).

ORGANISM(S): Homo sapiens

PROVIDER: GSE210104 | GEO | 2022/11/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The goal of this experiment was to characterize the genome-wide binding profiles of BET proteins, RPII, and H3K27Ac upon NEUORD1 knockout in H446 cells.

2022-11-23 | GSE210113 | GEO

BET Inhibitors Target the SCLC-N subtype of Small Cell Lung Cancer by Blocking NEUROD1 Transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as its transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. To investigate what genes are affected by NHWD-870 (a BET inhibitor) in SCLC-N subtype tumors in vivo, we performed an RNA-seq analysis of the tumor cells isolated from the LX22 PDX after NHWD-870 treatment at 2mg/kg via oral gavage daily for five days.

2022-11-23 | GSE210110 | GEO

BET inhibitors target the SCLC-N subtype of small-cell lung cancer by blocking NEUROD1 transactivation

Project description:Small cell lung cancer can be divided into several molecular subtypes based on the expression of four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1). These master factors have not been directly druggable, and we hypothesized that targeting their transcriptional coactivator(s) could provide an alternative approach. Here, we identify that BET bromodomain proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET bromodomain proteins in the SCLC genome. Targeting BET bromodomain proteins by BET inhibitors leads to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, and reduces SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes. The goals for this part of the study were: 1) to identify the NEUROD1 target genes in the SCLC-N subtype small cell lung cancer. To this end, we knocked out NEUROD1 in H446 cells (SCLC-N subtype) by CRISPR and assessed gene expression alterations in three knockout and three control clones. An integrated analysis of the RNA-seq data and the NEUROD1 ChIP-seq data was performed to identify the NEUROD1 target genes; 2) to assess how NEUROD1 knockout affects the response to JQ1 (a BET inhibitor).

2022-11-23 | GSE210101 | GEO

BET bromodomain proteins regulate enhancer function during adipogenesis

Project description:Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in expression of PPARg and C/EBPa, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARg and C/EBPa expression are less well characterized. Here we show the bromodomain-containing protein, BRD4, regulates transcription of PPARg and C/EBPa. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super enhancers proximal to genes controlling adipocyte differentiation. BET bromodomain inhibition impedes BRD4 occupancy at these de novo enhancers and disrupts transcription of Pparg and Cebpa, thereby blocking adipogenesis. Furthermore, silencing of these BRD4-occupied distal regulatory elements at the Pparg locus by CRISPRi demonstrates a critical role for these enhancers in the control of Pparg gene expression and adipogenesis in 3T3L1s. Together, these data establish BET bromodomain proteins as time- and context-dependent coactivators of the adipocyte cell state transition.

2018-03-07 | GSE109940 | GEO

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [ChIP-Seq]

Project description:Heart failure is driven by the interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. Coordinate activation of developmental, inflammatory, fibrotic and growth regulators underlies the hallmark phenotypes of pathologic cardiac hypertrophy and contractile failure. While transactivation in this context is known to be associated with recruitment of histone acetyl-transferase enzymes and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in heart failure. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during the evolution of heart failure. BET inhibition suppresses cardiomyocyte hypertrophy in a cell-autonomous manner, confirmed by RNA interference in vitro. Following both pressure overload and neurohormonal stimulation, BET inhibition potently attenuates pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to heart failure pathogenesis. Specifically, BET bromodomain inhibition in mice abrogates pathology-associated pause release and transcriptional elongation, thereby preventing activation of cardiac transcriptional pathways relevant to the gene expression profile of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in heart failure. ChIP-Seq of mouse heart tissues from mice induced with heart failure and treated with JQ1 BET bromodomain inhibitor

2013-08-06 | E-GEOD-46668 | biostudies-arrayexpress

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [NRVM Expression]

Project description:Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF. Gene expression analysis of neonatal rat ventricular mycotes (NRVM) subjected to phenylephrine (PE) treatment followed by treatment with vehicle (DMSO) or the BET bromodomain inhibitor JQ1

2013-08-06 | E-GEOD-48111 | biostudies-arrayexpress

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [Mouse Heart Expression]

Project description:Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF. Gene expression analysis of mouse hearts subjected to either trans aortic constriction (TAC) or sham surgeries followed by treamtent with dmso vehicle or the BET bromodomain inhibitor JQ1

2013-08-06 | E-GEOD-48110 | biostudies-arrayexpress

Inhibition of Karyopherin β1-mediated nuclear import of lineage-defining TFs in small cell lung cancer

Project description:Extensive genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on expression of lineage-defining transcription factors including ASCL1 and NEUROD1, which together account for ~80% of this disease. ASCL1 and NEUROD1 activate SCLC oncogene expression and drive distinct transcriptional programs. ASCL1 is also required for tumorigenesis in SCLC mouse models, and both ASCL1 and NEUROD1 maintain the in vitro growth and oncogenic properties of ASCL1+ or NEUROD1+ SCLC cell lines. Strategies to inhibit ASCL1 and NEUROD1 may therefore represent an attractive, targeted SCLC therapy and provide a tool to investigate the underlying plasticity of the predominant SCLC subtypes. However, ASCL1 and NEUROD1 have long been considered “undruggable” vulnerabilities. Here, we use a proteomic approach to identify Karyopherin β1 (KPNB1) as a nuclear import receptor for ASCL1 and NEUROD1 in SCLC, and demonstrate that the inhibition of KPNB1 using a variety of genetic or pharmacological approaches leads to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacological targeting of KPNB1 preferentially disrupts ASCL1/NEUROD1+ SCLC cell line growth in vitro and ASCL1+ tumor growth in an in vivo patient derived xenograft (PDX) model of SCLC.

2022-09-20 | GSE185187 | GEO

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (ChIP-seq)

Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors ChIP-seq analysis performed on three ASCL1high and two NEUROD1high human SCLC cell lines to identify ASCL1 and/or NEUROD1 binding sites in these two types of cells. Also, we performed ChIP-seq for Ascl1 binding sites in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

2016-07-21 | E-GEOD-69394 | biostudies-arrayexpress

Distinct Function for ASCL1 and NEUROD1 in Pulmonary Neuroendocrine Tumors (RNA-seq)

Project description:Small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are high-grade pulmonary neuroendocrine tumors. The neural basic helix-loop-helix (bHLH) transcription factors ASCL1 and NEUROD1 have been shown to play crucial roles in promoting the malignant behavior and survival of human SCLC cell lines. In this study, we find ASCL1 and NEUROD1 identify distinct neuroendocrine tumors, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1 and NEUROD1 are often bound in super-enhancers that are associated with highly expressed genes in their respective SCLC cell lines suggesting different cell lineage of origin for these tumors. ASCL1 targets oncogenic genes such as MYCL1, RET, and NFIB, while NEUROD1 targets the oncogenic gene MYC. Although ASCL1 and NEUROD1 regulate different genes, many of these gene targets commonly contribute to neuroendocrine and cell migration function. ASCL1 in particular also regulates genes in the NOTCH pathway and genes important in cell-cycle dynamics. Finally, we demonstrate ASCL1 but not NEUROD1 is required for SCLC and LCNEC tumor formation in current in vivo genetic mouse models of pulmonary neuroendocrine tumors RNA-seq analysis performed on two ASCL1high and two NEUROD1high human SCLC cell lines to identify gene expression patterns in these cells. Also, we performed RNA-seq in mouse neuroendocrine lung tumors obtained from Trp53;Rb1;Rbl2 triple knockout model mice treated with Adeno-CMVCRE intratracheally.

2016-07-21 | E-GEOD-69393 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data