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Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown.

ABSTRACT: Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown.

PROVIDER: PRJNA852538 | ENA |

REPOSITORIES: ENA

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Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [Ascl1_Ngn2_RNAseq_timecourse]

Project description:Two closely related proneural bHLH transcription factors, Ascl1 and Ngn2, both can induce mouse embryonic stem cells to differentiate into induced neurons. Although Ascl1 and Ngn2 induced transcriptional programs partially overlap, it is not known whether the differences translate into the distinct mechanisms. We found that both transcription factors induce mutually exclusive side populations by binding and inducing different lineage drivers. Furthermore, Ascl1 rapidly dismantles the pluripotency network and installs neuronal and trophoblast cell fates, while Ngn2 generates a neural stem cell-like intermediate supported by incomplete shutdown of the pluripotency network. Using CRISPR-Cas9 knockout screening, we revealed differential genetic dependencies between Ascl1 and Ngn2. Specifically, Ascl1 is more dependent on factors including Tcf7l1, that regulate pluripotency and cell cycle. In the absence of the pluripotency network repressor Tcf7l1 Ascl1 is still able to repress the core pluripotency genes, however failed to exit cell cycle. Overexpression of Cdkn1c induced cell cycle exit and restored the generation of neurons. This study illuminates two different mechanistic approaches to convert ESC to induced neurons: rapid shutdown of the initial state while installing a terminal cell identity versus repurposing the initial gene regulatory network to allow generation of neurons via intermediate states. Understanding the precise mechanism and the variety of cell states induced is essential to design efficient cell replacement therapeutic applications or precise tools for disease modelling.

2023-07-17 | GSE208199 | GEO

Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [CRISPR-UMI]

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Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [RNA-Seq]

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Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [ChIP-Seq]

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Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [Ascl1_Ngn2_RNAseq_timecourse]

Project description:Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [Ascl1_Ngn2_RNAseq_timecourse]

| PRJNA858796 | ENA

Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [RNA-Seq]

Project description:Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [RNA-Seq]

| PRJNA852541 | ENA

Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [CRISPR-UMI]

Project description:Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [CRISPR-UMI]

| PRJNA852540 | ENA

Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown. [ChIP-Seq]

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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

Induction of neurons from mouse ESC by the bHLH factors Ascl1 and Ngn2 shows distinct genetic dependencies, pluripotency exit, and cell cycle shutdown.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-17 | GSE206872 | GEO