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.

Metadata

Item Type:	Article
Authors/Creators:	Gerrard, DT Berry, AA Jennings, RE Birket, MJ Zarrineh, P Garstang, MG Withey, SL Short, P Jiménez-Gancedo, S Firbas, PN Donaldson, I Sharrocks, AD Hanley, KP Hurles, ME Gomez-Skarmeta, JL Bobola, N Hanley, NA
Copyright, Publisher and Additional Information:	© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Keywords:	Anatomy; Organogenesis
Dates:	Published: December 2020 Published (online): 6 August 2020 Accepted: 18 June 2020
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	10 Sep 2020 15:02
Last Modified:	10 Sep 2020 15:02
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-020-17305-2
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:165283

Download

Published Version

Filename: s41467-020-17305-2.pdf

Licence: CC-BY 4.0

CLICK TO DOWNLOAD

CORE (COnnecting REpositories)

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

Abstract

Metadata

Download

Published Version

Export

Statistics