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Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons.

ABSTRACT: 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.

SUBMITTER: Inglis GAS

PROVIDER: S-EPMC7471504 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons.

Inglis George Andrew S GAS Zhou Ying Y Patterson Dillon G DG Scharer Christopher D CD Han Yanfei Y Boss Jeremy M JM Wen Zhexing Z Escayg Andrew A

Human molecular genetics 20200801 15

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 stud ...[more]

PMID: 32794569

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Project description:RationaleThere is growing evidence that common variants and rare sequence alterations in regulatory sequences can result in birth defects or predisposition to disease. Congenital heart defects are the most common birth defect and have a clear genetic component, yet only a third of cases can be attributed to structural variation in the genome or a mutation in a gene. The remaining unknown cases could be caused by alterations in regulatory sequences.ObjectiveIdentify regulatory sequences and gene expression networks that are active during organogenesis of the human heart. Determine whether these sites and networks are enriched for disease-relevant genes and associated genetic variation.Methods and resultsWe characterized ChromHMM (chromatin state) and gene expression dynamics during human heart organogenesis. We profiled 7 histone modifications in embryonic hearts from each of 9 distinct Carnegie stages (13-14, 16-21, and 23), annotated chromatin states, and compared these maps to over 100 human tissues and cell types. We also generated RNA-sequencing data, performed differential expression, and constructed weighted gene coexpression networks. We identified 177 412 heart enhancers; 12 395 had not been previously annotated as strong enhancers. We identified 92% of all functionally validated heart-positive enhancers (n=281; 7.5× enrichment; P<2.2×10-16). Integration of these data demonstrated novel heart enhancers are enriched near genes expressed more strongly in cardiac tissue and are enriched for variants associated with ECG measures and atrial fibrillation. Our gene expression network analysis identified gene modules strongly enriched for heart-related functions, regulatory control by heart-specific enhancers, and putative disease genes.ConclusionsWell-connected hub genes with heart-specific expression targeted by embryonic heart-specific enhancers are likely disease candidates. Our functional annotations will allow for better interpretation of whole genome sequencing data in the large number of patients affected by congenital heart defects.

Dataset Information

Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons.

Publications

Transcriptomic and epigenomic dynamics associated with development of human iPSC-derived GABAergic interneurons.

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