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

Dave T. Gerrard, Andrew A. Berry, Rachel E. Jennings, Matthew J. Birket, Peyman Zarrineh, Myles G. Garstang, Sarah L. Withey, Patrick Short, Sandra Jiménez-Gancedo, Panos N. Firbas, Ian Donaldson, Andrew D. Sharrocks, Karen Piper Hanley, Matthew E. Hurles, José Luis Gomez-Skarmeta, Nicoletta Bobola and Neil A. Hanley ()
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Dave T. Gerrard: University of Manchester
Andrew A. Berry: University of Manchester
Rachel E. Jennings: University of Manchester
Matthew J. Birket: University of Manchester
Peyman Zarrineh: University of Manchester
Myles G. Garstang: University of Manchester
Sarah L. Withey: University of Manchester
Patrick Short: Wellcome Genome Campus
Sandra Jiménez-Gancedo: Consejo Superior de Investigacionnes Cientificas/Universidad Pablo de Olavide/Junta de Analucía
Panos N. Firbas: Consejo Superior de Investigacionnes Cientificas/Universidad Pablo de Olavide/Junta de Analucía
Ian Donaldson: University of Manchester
Andrew D. Sharrocks: University of Manchester
Karen Piper Hanley: University of Manchester
Matthew E. Hurles: Wellcome Genome Campus
José Luis Gomez-Skarmeta: Consejo Superior de Investigacionnes Cientificas/Universidad Pablo de Olavide/Junta de Analucía
Nicoletta Bobola: University of Manchester
Neil A. Hanley: University of Manchester

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17305-2

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