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Transcriptome analysis of small molecule-mediated astrocyte-to-neuron reprogramming

ABSTRACT: Transcriptome analysis of small molecule-mediated astrocyte-to-neuron reprogramming

PROVIDER: PRJNA506035 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8206870.fastq.gz	Fastqsanger.gz
	SRR8206880.fastq.gz	Fastqsanger.gz
	SRR8206871.fastq.gz	Fastqsanger.gz
	SRR8206881.fastq.gz	Fastqsanger.gz
	SRR8206872.fastq.gz	Fastqsanger.gz

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Transcriptome Analysis of Small Molecule-Mediated Astrocyte-to-Neuron Reprogramming.

Project description:Chemical reprogramming of astrocytes into neurons represents a promising approach to regenerate new neurons for brain repair, but the underlying mechanisms driving this trans-differentiation process are not well understood. We have recently identified four small molecules - CHIR99021, DAPT, LDN193189, and SB431542 - that can efficiently reprogram cultured human fetal astrocytes into functional neurons. Here we employ the next generation of RNA-sequencing technology to investigate the transcriptome changes during the astrocyte-to-neuron (AtN) conversion process. We found that the four small molecules can rapidly activate the hedgehog signaling pathway while downregulating many glial genes such as FN1 and MYL9 within 24 h of treatment. Chemical reprogramming is mediated by several waves of differential gene expression, including upregulation of hedgehog, Wnt/β-catenin, and Notch signaling pathways, together with downregulation of TGF-β and JAK/STAT signaling pathways. Our gene network analyses reveal many well-connected hub genes such as repulsive guidance molecule A (RGMA), neuronatin (NNAT), neurogenin 2 (NEUROG2), NPTX2, MOXD1, JAG1, and GAP43, which may coordinate the chemical reprogramming process. Together, these findings provide critical insights into the molecular cascades triggered by a combination of small molecules that eventually leads to chemical conversion of astrocytes into neurons.

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Mitochondrial reprogramming using dCas9 boosts glia-to-neuron conversion

Project description:Astrocyte-to-neuron conversion has developed into a promising avenue for neuronal replacement therapy. Neurons depend critically on mitochondria function and often die by ferroptosis during the conversion process. Here we examined the extent of adequate mitochondrial reprogramming by morphology and proteome analysis. While mitochondria profoundly changed their morphology during Neurogenin2 (Neurog2) – or Achaete-scute homolog 1 (Ascl1)-mediated astrocyte-to-neuron reprogramming, we found neuron-specific mitochondrial proteins, here identified in a comprehensive proteome analysis of isolated mitochondria from primary neurons and astrocytes, to be only partially and at late stages regulated during the process. To improve this, we used dCas9 technology to induce neuron-specific mitochondrial proteins early during reprogramming. This resulted not only in increased conversion efficiency, but also in faster neuronal generation. Taken together, reprogramming mitochondria in a cell type-specific manner has powerful effects on astrocyte-to-neuron conversion, suggesting mitochondria to be a driving force in this process.

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Transcriptional changes and microRNA expression profiles during NeuroD1-mediated astrocyte-to-neuron conversion

Project description:To reveal the molecular mechanisms underlying astrocyte-to-neuron reprogramming, we performed RNA-seq analysis on human astrocyte cultures (HA1800) during NeuroD1(ND1)-mediated neuronal reprogramming.

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Transcriptome analysis of small molecule-mediated astrocyte-to-neuron reprogramming

Project description:Human astrocytes can be efficiently reprogrammed into functional neurons in culture by the addition of four small molecules. RNA-seq was performed to assess transcriptome alterations at different time points to characterize the molecular mechanisms.

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