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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: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Escherichia coli

PROVIDER: GSE206872 | GEO | 2023/07/17

REPOSITORIES: GEO

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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]

2023-07-17 | GSE206871 | GEO

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]

2023-07-17 | GSE206870 | GEO

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]

2023-07-17 | GSE206869 | GEO

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

| PRJNA852538 | ENA

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]

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. [ChIP-Seq]

| PRJNA852542 | ENA

Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3.

Project description:Factors that sustain self-renewal of mouse embryonic stem cells (ESCs) are well described. In contrast, the machinery regulating exit from pluripotency is ill defined. In a large-scale small interfering RNA (siRNA) screen, we found that knockdown of the tumor suppressors Folliculin (Flcn) and Tsc2 prevent ESC commitment. Tsc2 lies upstream of mammalian target of rapamycin (mTOR), whereas Flcn acts downstream and in parallel. Flcn with its interaction partners Fnip1 and Fnip2 drives differentiation by restricting nuclear localization and activity of the bHLH transcription factor Tfe3. Conversely, enforced nuclear Tfe3 enables ESCs to withstand differentiation conditions. Genome-wide location and functional analyses showed that Tfe3 directly integrates into the pluripotency circuitry through transcriptional regulation of Esrrb. These findings identify a cell-intrinsic rheostat for destabilizing ground-state pluripotency to allow lineage commitment. Congruently, stage-specific subcellular relocalization of Tfe3 suggests that Flcn-Fnip1/2 contributes to developmental progression of the pluripotent epiblast in vivo.

| S-EPMC3661979 | biostudies-literature

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