The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders
Gerrard, D. T.; Berry, A. A.; Jennings, R. E.; Birket, M.; Withey, S. J.; Short, P.; Jimenez-Gancedo, S.; Firbas, P.; Donaldson, I.; Sharrocks, A. D.; Piper Hanley, K.; Hurles, M. E.; Gomez-Skarmeta, J. L.; Bobola, N.; Hanley, N. A.
Show 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 in vitro stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we studied histone modifications across thirteen tissues during human organogenesis. We integrated the data with transcription to build the first overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partitioned into discrete states without showing bivalency. Key developmental gene sets were actively repressed outside of the appropriate organ. Candidate enhancers, functional in zebrafish, allowed imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allowed correlation to unanticipated target genes. Taken together, the data provide a new, comprehensive genomic framework for investigating normal and abnormal human development.
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