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An integrative transcriptomic atlas of organogenesis in human embryos.

ABSTRACT: Human organogenesis is when severe developmental abnormalities commonly originate. However, understanding this critical embryonic phase has relied upon inference from patient phenotypes and assumptions from in vitro stem cell models and non-human vertebrates. We report an integrated transcriptomic atlas of human organogenesis. By lineage-guided principal components analysis, we uncover novel relatedness of particular developmental genes across different organs and tissues and identified unique transcriptional codes which correctly predicted the cause of many congenital disorders. By inference, our model pinpoints co-enriched genes as new causes of developmental disorders such as cleft palate and congenital heart disease. The data revealed more than 6000 novel transcripts, over 90% of which fulfil criteria as long non-coding RNAs correlated with the protein-coding genome over megabase distances. Taken together, we have uncovered cryptic transcriptional programs used by the human embryo and established a new resource for the molecular understanding of human organogenesis and its associated disorders.

SUBMITTER: Gerrard DT

PROVIDER: S-EPMC4996651 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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An integrative transcriptomic atlas of organogenesis in human embryos.

Gerrard Dave T DT Berry Andrew A AA Jennings Rachel E RE Piper Hanley Karen K Bobola Nicoletta N Hanley Neil A NA

eLife 20160824

Human organogenesis is when severe developmental abnormalities commonly originate. However, understanding this critical embryonic phase has relied upon inference from patient phenotypes and assumptions from in vitro stem cell models and non-human vertebrates. We report an integrated transcriptomic atlas of human organogenesis. By lineage-guided principal components analysis, we uncover novel relatedness of particular developmental genes across different organs and tissues and identified unique t ...[more]

PMID: 27557446

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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

An integrative transcriptomic atlas of organogenesis in human embryos.

Publications

An integrative transcriptomic atlas of organogenesis in human embryos.

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