Deciphering NEUROD1's target genes and miRNAs: an integrative analysis in small cell lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270263 | GEO | 2025/06/28
REPOSITORIES: GEO
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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
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
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
2016-07-21 | GSE69394 | GEO
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
2016-07-21 | GSE69393 | GEO
Project description:Small cell lung cancer (SCLC) is divided into four subtypes based on specific transcription regulators: ASCL1, NEUROD1, POU2F3, and YAP1. Around 80% of SCLC cases show neuroendocrine markers, mainly ASCL1 (called SCLC-A) or NEUROD1 (called SCLC-N). In the past, these four subtypes were thought to be completely separate. However, recent studies have shown that they can change into one another. For example, SCLC-N can develop from SCLC-A. Additionally, ASCL1 and NEUROD1 can sometimes be expressed together, although this combined subtype is not well understood. Our previous research (PMID: 35789143) showed that ASCL1 controls certain microRNAs (miRNAs), which helps keep the subtypes separate. However, the exact way NEUROD1 controls transcription in SCLC, especially when it is co-expressed with ASCL1, is still unknown. To investigate transcriptional regulation, we used Cleavage Under Targets and Tagmentation (CUT&Tag) to confirm the binding sites of ASCL1 and NEUROD1 for double positive cells.
2025-06-28 | GSE277353 | GEO
Project description:Using a CRISPR-based autochthonous SCLC GEMM to study the consequences of KDM6A/UTX inactivation, we found that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors with open chromatin at the NEUROD1 promoter that express both ASCL1 and NEUROD1. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides a novel autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.
2023-06-09 | GSE228345 | GEO
Project description:ASCL1 is a neuroendocrine-lineage-specific oncogenic driver of small cell lung cancer (SCLC), highly expressed in a significant fraction of tumors. However, ~25% of human SCLC are ASCL1-low and associated with low-neuroendocrine fate and high MYC expression. Using genetically-engineered mouse models (GEMMs), we show that alterations in Rb1/Trp53/Myc in the mouse lung induce an ASCL1+ state of SCLC in multiple cell types. Genetic depletion of ASCL1 in MYC-driven SCLC dramatically inhibits tumor initiation, but surprisingly converts tumors to a SOX9+ mesenchymal/neural-crest-stem-like state that has the capacity to differentiate into RUNX2+bone tumors. ASCL1 represses SOX9 expression, as well as WNT and NOTCH developmental pathways, consistent with human gene expression data. SCLC demonstrates remarkable cell fate plasticity with ASCL1 repressing the emergence of non-endodermal stem-like fates that have the capacity for bone differentiation. Here, we perform ChIP on RPM tumors against ASCL1, NEUROD1, and H3k27Ac to view binding profiles and identify target genes of ASCL1 and NEUROD1.
2021-05-22 | GSE155690 | GEO
Project description:Molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 knockdown resulted in decreased and increased expression of miR-375 and miR-455-3p, respectively. Analyses of publicly available transcriptome datasets suggested that miR-375 induced by ASCL1 is involved in YAP1 suppression whereas miR-455-3p is higher in non-neuroendocrine SCLC cells lacking ASCL1 expression.
2021-07-25 | GSE180315 | GEO
Project description:Molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 knockdown resulted in decreased and increased expression of miR-375 and miR-455-3p, respectively. Analyses of publicly available transcriptome datasets suggested that miR-375 induced by ASCL1 is involved in YAP1 suppression whereas miR-455-3p is higher in non-neuroendocrine SCLC cells lacking ASCL1 expression.
2021-07-25 | GSE180314 | GEO
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