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Rapid and efficient conversion of common marmoset fibroblasts into mature and functional neurons by overexpression of ASCL1 and microRNA-9/9*-124

ABSTRACT: Rapid and efficient conversion of common marmoset fibroblasts into mature and functional neurons by overexpression of ASCL1 and microRNA-9/9*-124

PROVIDER: PRJNA639333 | ENA |

REPOSITORIES: ENA

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Rapid and efficient conversion of common marmoset fibroblasts into mature and functional neurons by overexpression of ASCL1 and microRNA-9/9*-124

Project description:The common marmoset (marmoset; Callithrix jacchus) has been attracting much attention especially in the research fields of biomedical science and neuroscience, because of its potential to recapitulate the complex and multidimensional phenotypes of human diseases. Taking these advantages, several transgenic models have been reported so far. However, there remain several issues such as (i) it takes years to generate the late-onset disease models, and (ii) the onset age and severity of phenotypes can vary among individual animals due to their differences in the genetic background. In the present study, we established an efficient and rapid direct neuronal induction method (induced Neuron; iN) from embryonic and adult marmoset fibroblasts. This iN method is a minimally invasive approach to investigate cellular-level phenotypes in the marmoset brain. We overexpressed microRNA-9/9*-124 and a transcription factor ASCL1 in fibroblasts with a small molecule cocktail that ameliorates neuronal induction. The resultant iN cells from both embryonic and adult marmoset fibroblasts showed standard neuronal characteristic within 2 weeks, including neuronal specific gene expression and neuronal membrane spontaneous firing activity. Thus, this novel neuronal induction method may offer a new tool for investigating neurological phenotypes in vitro without collecting living brain tissue in non-human primate neurological disease models.

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MicroRNAs and Ascl1 facilitate direct conversion of porcine fibroblasts into induced neurons

Project description:Direct neuronal conversion describes the process of generating induced neurons from somatic cells such as fibroblasts by overexpressing cell type-specific transcription factors. This was first achieved by expressing Brn2, Ascl1 and MytL1 in mouse fibroblasts, and was later achieved in human cells by inclusion of additional factors such as NeuroD1. Here, we present the first protocol for directly converting porcine fibroblasts into induced neurons. We used lentivirus-mediated delivery of previously identified neuronal-specifying transcription factors and microRNAs and evaluated morphology and neuronal marker expression after ten days of conversion. We found that Ascl1 and microRNAs, miR-9/9* and miR-124 together generated more neuronal cells than other conditions tested. The porcine induced neurons expressed common mature markers such as MAP2 and Synaptophysin after four weeks of conversion. Transcriptomic analysis revealed that fibroblast-specific signatures were silenced early in the conversion process, while the neuronal programs increased and matured during conversion. We generated a heterogenous population of glutamatergic and GABAergic neurons.

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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.

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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts.

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Project description:Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

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PRRX2 and HEY2 double knock-down facilitates ASCL1-induced neuron conversion in human dermal fibroblasts II

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Primed to naïve-like conversion of the common marmoset embryonic stem cells

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Primed to naïve-like conversion of the common marmoset embryonic stem cells

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MicroRNAs and Ascl1 facilitate direct conversion of porcine fibroblasts into induced neurons

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