Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons
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ABSTRACT:
PROVIDER: PRJNA605871 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11059800_1.fastq.gz | Fastqsanger.gz | |||
| SRR11059800_2.fastq.gz | Fastqsanger.gz | |||
| SRR11059801_1.fastq.gz | Fastqsanger.gz | |||
| SRR11059801_2.fastq.gz | Fastqsanger.gz | |||
| SRR11059802_1.fastq.gz | Fastqsanger.gz |
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Project description:GABAergic interneurons (GINs) are a heterogeneous class of inhibitory neurons that collectively maintain normal neuronal excitability and network activity. Identification of the genetic regulatory elements and transcription factors that contribute toward GIN function may provide new insight into the pathways underlying proper GIN activity, while also indicating potential therapeutic targets for GIN-associated disorders, such as epilepsy and schizophrenia. In this study, we examined temporal changes in gene expression and chromatin accessibility by collecting human iPSC-derived GINs at three time points for transcriptomic and epigenomic analysis: neural progenitor cells at 22 days post-differentiation (D22), then GINs at D50 and D78. Collectively, these data provide a resource for examining the molecular networks regulating normal GIN functionality.
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Project description:Transplantation of GABAergic interneurons (INs) can sustain long-standing benefits in animal models of epilepsy and other neurological disorders. In a therapeutic perspective, a renewable source of functional GABAergic INs is needed. Here, we identified five factors (Foxg1, Sox2, Ascl1, Dlx5 and Lhx6) able to convert fibroblasts directly into induced GABAergic INs (iGABA-INs), displaying the molecular signature of telencephalic INs. The selected factors recapitulate in fibroblasts the activation of transcriptional networks required for the specification of GABAergic fate during telencephalon development. iGABA-INs exhibited progressively maturing firing patterns comparable to those of cortical INs, had synaptic currents and released GABA. Importantly, upon grafting in the hippocampus, iGABA-INs survived, matured and their optogenetic stimulation triggered GABAergic transmission and inhibited the activity of connected granule cells. The five factors also converted human cells into functional GABAergic neurons. These properties define iGABA-INs as a promising tool for disease modeling and cell-based therapeutic approaches. Comparison of iGABA-INs transcriptional profile with those of starting fibroblasts and GAD67-GFP+ cortical interneurons.
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Project description:GABAergic interneurons (GINs) are a heterogeneous population of inhibitory neurons that collectively contribute to the maintenance of normal neuronal excitability and network activity. Identification of the genetic regulatory elements and transcription factors that contribute toward GIN function may provide new insight into the pathways underlying proper GIN activity while also indicating potential therapeutic targets for GIN-associated disorders, such as schizophrenia and epilepsy. In this study, we examined the temporal changes in gene expression and chromatin accessibility during GIN development by performing transcriptomic and epigenomic analyses on human induced pluripotent stem cell-derived neurons at 22, 50 and 78 days (D) post-differentiation. We observed 13?221 differentially accessible regions (DARs) of chromatin that associate with temporal changes in gene expression at D78 and D50, relative to D22. We also classified families of transcription factors that are increasingly enriched at DARs during differentiation, indicating regulatory networks that likely drive GIN development. Collectively, these data provide a resource for examining the molecular networks regulating GIN functionality.
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