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; Neil A. Hanley

doi:10.1038/s41467-020-17305-2

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, Neil A. Hanley^*

^*Corresponding author for this work

Medicine and Health

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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.

Original language	English
Article number	3920
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17305-2
Publication status	Published - 1 Dec 2020

Bibliographical note

Funding Information:
We are very grateful to all women who consented to take part in our research programme and for the assistance of research nurses and clinical colleagues at the Manchester University NHS Foundation Trust. We thank Peter Briggs and Andy Hayes of the Bioinformatics and Genomic Technologies Core Facilities at the University of Manchester. The work was supported by Wellcome grants 088566, 097820 and 105610, with additional support from MRC project grants MR/L009986/1 to N.B. and N.A.H., MR/ J003352/1 to K.P.H., and MR/000638/1 and MR/S036121/1 to N.A.H. R.E.J. was an MRC clinical research training fellow, and S.J.W. was an MRC doctoral account PhD student. J. L.G.S. was supported by the Marató TV3 Fundacion (Grant No. 201611).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Gerrard, D. T., Berry, A. A., Jennings, R. E., Birket, M. J., Zarrineh, P., Garstang, M. G., Withey, S. L., Short, P., Jiménez-Gancedo, S., Firbas, P. N., Donaldson, I., Sharrocks, A. D., Hanley, K. P., Hurles, M. E., Gomez-Skarmeta, J. L., Bobola, N., & Hanley, N. A. (2020). Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders. Nature Communications, 11(1), Article 3920. https://doi.org/10.1038/s41467-020-17305-2

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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.",

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note = "Funding Information: We are very grateful to all women who consented to take part in our research programme and for the assistance of research nurses and clinical colleagues at the Manchester University NHS Foundation Trust. We thank Peter Briggs and Andy Hayes of the Bioinformatics and Genomic Technologies Core Facilities at the University of Manchester. The work was supported by Wellcome grants 088566, 097820 and 105610, with additional support from MRC project grants MR/L009986/1 to N.B. and N.A.H., MR/ J003352/1 to K.P.H., and MR/000638/1 and MR/S036121/1 to N.A.H. R.E.J. was an MRC clinical research training fellow, and S.J.W. was an MRC doctoral account PhD student. J. L.G.S. was supported by the Marat{\'o} TV3 Fundacion (Grant No. 201611). Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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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 2020, 'Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders', Nature Communications, vol. 11, no. 1, 3920. https://doi.org/10.1038/s41467-020-17305-2

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AU - Zarrineh, Peyman

AU - Garstang, Myles G.

AU - Withey, Sarah L.

AU - Short, Patrick

AU - Jiménez-Gancedo, Sandra

AU - Firbas, Panos N.

AU - Donaldson, Ian

AU - Sharrocks, Andrew D.

AU - Hanley, Karen Piper

AU - Hurles, Matthew E.

AU - Gomez-Skarmeta, José Luis

AU - Bobola, Nicoletta

AU - Hanley, Neil A.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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