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FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis

ABSTRACT: FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3 – the FOXO isoform associated with exceptional human longevity – preserves adult neural stem cell pools. Here we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors and FOXO3 shares common targets with the pro-neuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis in vivo. Our study identifies a genome-wide interaction between the pro-longevity transcription factor FOXO3 and the cell fate determinant ASCL1, and raises the possibility that FOXO3’s ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool.

ORGANISM(S): Mus musculus

PROVIDER: GSE48336 | GEO | 2013/08/13

SECONDARY ACCESSION(S): PRJNA209713

REPOSITORIES: GEO

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FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis

Project description:FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3 – the FOXO isoform associated with exceptional human longevity – preserves adult neural stem cell pools. Here we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors and FOXO3 shares common targets with the pro-neuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis in vivo. Our study identifies a genome-wide interaction between the pro-longevity transcription factor FOXO3 and the cell fate determinant ASCL1, and raises the possibility that FOXO3’s ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool. ChIP-seq profiles of two transcription factors (FOXO3 and ASCL1) and three histone marks (H3K4me1, H3K4me3 and H3K27me3) in adult mouse neural progenitor cells.

2013-08-13 | E-GEOD-48336 | biostudies-arrayexpress

Regulation of cortical folding by niche progenitor cells that co-express cross-repressive transcription factors Neurog2 and Ascl1

Project description:Humans exemplify gyrencephalic species with folded cerebral cortices, contrasting with lissencephalic mammals such as mice. Here we investigated how proneural genes Neurog2 and Ascl1 control cortical folding by regulating neurogenic patterns. Cortical neural progenitor cells (NPCs) stratify into four pools (proneural negative, Neurog2+, Ascl1+, double+) that are distributed evenly in mouse cortices and modular in gyrencephalic macaque cortices and pseudo-folded human cerebral organoids. Each pool has distinct developmental potentials, transcriptomes, epigenomes, and gene regulatory networks. Neurog2-Ascl1 form a bistable toggle switch double+ NPCs to prevent lineage commitment observed in single+ NPCs. Neurog2 and Ascl1 act redundantly to control neurogenic timing, with NPCs precociously depleted in Neurog2-/-;Ascl1-/- cortices. Finally, selective killing of Neurog2/Ascl1 double+ NPCs using Neurog2/Ascl1 split-Cre;Rosa-DTA transgenics breaks neurogenic symmetry in mice by locally disrupting Notch signaling, leading to cortical folding. Our findings suggest that Neurog2/Ascl1 double+ NPCs are Notch-ligand expressing ‘niche’ cells that regulate neurogenic continuity and cortical gyrification.

2021-05-26 | GSE84120 | GEO

A novel role for ASCL1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT function

Project description:Maternally expressed proteins function in vertebrates to establish the major body axes of the embryo, and to establish a pre-pattern that sets the stage for later acting zygotic signals. This pre-pattern drives the propensity of Xenopus animal cap cells to adopt neural fates under various experimental conditions. Previous studies found that the maternally expressed transcription factor, encoded by the Xenopus achaete-scute like gene ascl1, is enriched at the animal pole. Asc1l is a bHLH protein involved in neural development, but its maternal function has not been studied. In this study, we have performed a series of gain and loss of function experiments on maternal ascl1, and present three novel findings. First, Ascl1 is a repressor of mesendoderm induced by VegT, but not of Nodal induced mesendoderm. Secondly, a previously uncharacterized N-terminal domain of Ascl1 interacts with HDAC1 to inhibit mesendoderm gene expression. This N-terminal domain is dispensable for its neurogenic function, indicating that Ascl1 has acts by different mechanisms at different times. Ascl1-mediated repression of mesendoderm genes was dependent on HDAC activity and accompanied by histone deacetylation in the promoter regions of VegT targets. Finally, maternal Ascl1 is required for animal cap cells to retain their competence to adopt neural fates. These results establish maternal Asc1l as a key factor in establishing the pre-pattern of the early embryo, acting in opposition to VegT and biasing the animal pole to adopt neural fates. The data presented here significantly extend our understanding of early embryonic pattern formation. Examination of genes expression in control (cMO) and Ascl1 MO knockdown (AMOs) embryos by deep sequencing.

2016-01-16 | E-GEOD-76915 | biostudies-arrayexpress

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

Role of ASCL1 in human neural development

Project description:As a proneural gene, ASCL1 was reported to be important to neurogenesis. To better illustrate the role of ASCL1 in human telencephalon development, we genetically engineered an ASCL1 knockout (KO) hESC line and ASCL1 rescue (RE) hESC line, and then preformed RNA sequencing when WT, KO and RE were differentiated into neural progenitors in vitro. Our results showed that ASCL1 KO hESCs could be regularly maintained in vitro, and could be efficiently specified into neuroectoderm cells and following telencephalic neural progenitors. Remarkably, dorsal progenitors-derived from ASCL1 KO hESCs failed to differentiate into DCX positive neuroblasts. In addition, dorsal and ventral progenitors retained higher expression of VZ/ESVZ genes but had much lower expression of LSVZ genes after KO of ASCL1. Re-introducing of ASCL1 in KO hESCs through a doxycycline (Dox) inducible overexpression system reversed the gene expression changes induced by cortical progenitors with ASCL1 KO. Taken all these together, our results revealed a pivotal role of ASCL1 in both dorsal and ventral telencephalic development by progressing the cycling progenitors within the ESVZ to post-mitotic early born neurons in the LSVZ in human telencephalon.

2022-12-21 | GSE149096 | GEO

Single cell transcriptomes of neurally differentiated wildtype and ASCL1-KO human iPSCs, in the presence of NOTCH inhibitor DAPT [scRNA-seq]

Project description:The roles of neurogenic pioneer transcription factors and chromatin remodelers have been characterized in that process in developing animal models and cancers. However how these factors interact with each other to regulate cell state transitions in human neurogenesis remains unclear. Here we investigated the activity of the pioneer proneural factor ASCL1 in an in vitro model of human neurogenesis. We found that ASCL1 expression characterizes a transitional state from cycling neural progenitor to post-mitotic neuron, and ASCL1 knockout impedes progenitor neuronal differentiation. ASCL1 binds to genomic targets to regulate loci promoting differentiation by different mechanisms. Acting as a classical pioneer transcription factor, its binding to compacted chromatin is required to induce transcriptional activity. At other loci, it acts as a non-pioneer chromatin remodeler, accessing permissive chromatin to further increase chromatin accessibility. We show that ASCL1 interacts with ATPase-active BAF mSWI/SNF chromatin remodelers at cis-regulatory elements, altering the chromatin regulatory landscape at a subset of target genes. This cooperative function is predominant at sites of non-pioneer chromatin remodeler function where ASCL1 requires mSWI/SNF for DNA binding while ASCL1 classical pioneer activity does not involve significant mSWI/SNF binding. Our work establishes novel roles for ASCL1 and for an interaction with mSWI/SNF in regulating epigenetic states in human neurogenesis.

2023-03-14 | GSE214700 | GEO

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

2016-07-21 | GSE69394 | GEO

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

2016-07-21 | GSE69393 | GEO

Microglia suppress Ascl1-induced retinal regeneration in mice.

Project description:The innate immune system plays key roles in tissue regeneration. For example, microglia promote neurogenesis in Müller glia in birds and fish after injury. Although mammalian retina does not normally regenerate, neurogenesis can be induced in mouse Müller glia by Ascl1, a proneural transcription factor. We show that in mice, microglia inhibit the Ascl1-mediated retinal regeneration, suggesting the innate immune system limits the regenerative response to injury.

2020-12-30 | GSE161394 | GEO

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