RT Journal Article
SR Electronic
T1 The epigenomic landscape regulating organogenesis in human embryos linked to developmental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 691766
DO 10.1101/691766
A1 Dave T. Gerrard
A1 Andrew A. Berry
A1 Rachel E. Jennings
A1 Matthew J Birket
A1 Sarah J Withey
A1 Patrick Short
A1 Sandra Jiménez-Gancedo
A1 Panos N Firbas
A1 Ian Donaldson
A1 Andrew D. Sharrocks
A1 Karen Piper Hanley
A1 Matthew E Hurles
A1 José Luis Gomez-Skarmeta
A1 Nicoletta Bobola
A1 Neil A. Hanley
YR 2019
UL http://biorxiv.org/content/early/2019/07/06/691766.abstract
AB 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.