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Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders.

ABSTRACT: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.

SUBMITTER: Gerrard DT

PROVIDER: S-EPMC7413392 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders.

Gerrard Dave T DT Berry Andrew A AA Jennings Rachel E RE Birket Matthew J MJ Zarrineh Peyman P Garstang Myles G MG Withey Sarah L SL Short Patrick P Jiménez-Gancedo Sandra S Firbas Panos N PN Donaldson Ian I Sharrocks Andrew D AD Hanley Karen Piper KP Hurles Matthew E ME Gomez-Skarmeta José Luis JL Bobola Nicoletta N Hanley Neil A NA

Nature communications 20200806 1

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates ...[more]

PMID: 32764605

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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

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders.

Publications

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders.

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