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

Dave T. Gerrard; Andrew Berry; Rachel Jennings; Matthew Birket; Peyman Zarrineh; Myles Garstang; Sarah Withey; Patrick  Short; Sandra Jiménez-Ganced; Panos N. Firbas; Ian Donaldson; Andy Sharrocks; Karen Piper Hanley; Matthew E. Hurles; Jose Luis Gomez-Skarmeta; Nicoletta Bobola; Neil Hanley

doi:https://doi.org/10.1038/s41467-020-17305-2

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

Dave T. Gerrard, Andrew Berry, Rachel Jennings, Matthew Birket, Peyman Zarrineh, Myles Garstang, Sarah Withey, Patrick Short, Sandra Jiménez-Ganced, Panos N. Firbas, Ian Donaldson, Andy Sharrocks, Karen Piper Hanley, Matthew E. Hurles, Jose Luis Gomez-Skarmeta, Nicoletta Bobola, Neil Hanley

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

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
Pages (from-to)	3920
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17305-2
Publication status	Published - 6 Aug 2020

Keywords

Animals
Animals, Genetically Modified
Databases, Genetic
Developmental Disabilities/genetics
Enhancer Elements, Genetic
Epigenesis, Genetic
Gene Expression Regulation, Developmental
Histone Code/genetics
Humans
Models, Genetic
Mutation
Organogenesis/genetics
Promoter Regions, Genetic
Tissue Distribution
Transcription Factors/metabolism
Zebrafish/embryology

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https://doi.org/10.1038/s41467-020-17305-2Licence: CC BY

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

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title = "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.",

keywords = "Animals, Animals, Genetically Modified, Databases, Genetic, Developmental Disabilities/genetics, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Histone Code/genetics, Humans, Models, Genetic, Mutation, Organogenesis/genetics, Promoter Regions, Genetic, Tissue Distribution, Transcription Factors/metabolism, Zebrafish/embryology",

author = "Gerrard, {Dave T.} and Andrew Berry and Rachel Jennings and Matthew Birket and Peyman Zarrineh and Myles Garstang and Sarah Withey and Patrick Short and Sandra Jim{\'e}nez-Ganced and Firbas, {Panos N.} and Ian Donaldson and Andy Sharrocks and {Piper Hanley}, Karen and Hurles, {Matthew E.} and Gomez-Skarmeta, {Jose Luis} and Nicoletta Bobola and Neil Hanley",

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). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = aug,

day = "6",

doi = "https://doi.org/10.1038/s41467-020-17305-2",

language = "English",

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pages = "3920",

journal = "Nature Communications",

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Gerrard, DT, Berry, A, Jennings, R , Birket, M, Zarrineh, P, Garstang, M, Withey, S, Short, P, Jiménez-Ganced, S, Firbas, PN, Donaldson, I , Sharrocks, A , Piper Hanley, K, Hurles, ME, Gomez-Skarmeta, JL, Bobola, N & Hanley, N 2020, 'Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders', Nature Communications, vol. 11, no. 1, 3920, pp. 3920. https://doi.org/10.1038/s41467-020-17305-2

TY - JOUR

T1 - Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

AU - Gerrard, Dave T.

AU - Berry, Andrew

AU - Jennings, Rachel

AU - Birket, Matthew

AU - Zarrineh, Peyman

AU - Garstang, Myles

AU - Withey, Sarah

AU - Short, Patrick

AU - Jiménez-Ganced, Sandra

AU - Firbas, Panos N.

AU - Donaldson, Ian

AU - Sharrocks, Andy

AU - Piper Hanley, Karen

AU - Hurles, Matthew E.

AU - Gomez-Skarmeta, Jose Luis

AU - Bobola, Nicoletta

AU - Hanley, Neil

N1 - 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). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8/6

Y1 - 2020/8/6

N2 - 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.

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 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.

KW - Animals

KW - Animals, Genetically Modified

KW - Databases, Genetic

KW - Developmental Disabilities/genetics

KW - Enhancer Elements, Genetic

KW - Epigenesis, Genetic

KW - Gene Expression Regulation, Developmental

KW - Histone Code/genetics

KW - Humans

KW - Models, Genetic

KW - Mutation

KW - Organogenesis/genetics

KW - Promoter Regions, Genetic

KW - Tissue Distribution

KW - Transcription Factors/metabolism

KW - Zebrafish/embryology

U2 - https://doi.org/10.1038/s41467-020-17305-2

DO - https://doi.org/10.1038/s41467-020-17305-2

M3 - Article

C2 - 32764605

VL - 11

SP - 3920

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3920

ER -

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

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Keywords

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