The genetic architecture of DNA replication timing in human pluripotent stem cells.

Acetylation Biological Variation, Population / genetics DNA Methylation DNA Replication Timing Datasets as Topic Female Gene Expression Regulation Genome, Human Histone Code / genetics Histones / metabolism Humans Male Pluripotent Stem Cells / metabolism Quantitative Trait Loci Transcription Factors / metabolism Whole Genome Sequencing

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
19 11 2021
Historique:
received: 17 08 2021
accepted: 29 10 2021
entrez: 20 11 2021
pubmed: 21 11 2021
medline: 24 12 2021
Statut: epublish

Résumé

DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome's replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs) - sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation.

Identifiants

DOI: 10.1038/s41467-021-27115-9 PMID: 34799581 PMC: PMC8604924
pubmed: 34799581
doi: 10.1038/s41467-021-27115-9
pii: 10.1038/s41467-021-27115-9
pmc: PMC8604924
doi:

Substances chimiques

Histones 0
Transcription Factors 0

Types de publication

Journal Article Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

6746

Subventions

Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : DP2 GM123495
Pays : United States
Organisme : Medical Research Council
ID : MR/R015724/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 211221/Z/18/Z
Pays : United Kingdom

Informations de copyright

© 2021. The Author(s).

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Auteurs

Qiliang Ding (Q)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Matthew M Edwards (MM)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.
ORCID: 0000-0001-9134-4666

Ning Wang (N)

Department of Pediatrics, Columbia University, New York, NY, 10032, USA.

Xiang Zhu (X)

Department of Statistics, Pennsylvania State University, University Park, 16801, PA, USA.
Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, 16801, PA, USA.
Department of Statistics, Stanford University, Stanford, CA, 94305, USA.
ORCID: 0000-0003-1134-6413

Alexa N Bracci (AN)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Michelle L Hulke (ML)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Ya Hu (Y)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.
New York Genome Center, New York, NY, 10013, USA.

Yao Tong (Y)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Joyce Hsiao (J)

Department of Human Genetics, University of Chicago, Chicago, IL, 60637, USA.

Christine J Charvet (CJ)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

Sulagna Ghosh (S)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.

Robert E Handsaker (RE)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
ORCID: 0000-0002-3128-3547

Kevin Eggan (K)

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
Howard Hughes Medical Institute, Harvard University, Cambridge, MA, 02138, USA.
ORCID: 0000-0003-4436-8467

Florian T Merkle (FT)

Wellcome Trust - Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
ORCID: 0000-0002-8513-2998

Jeannine Gerhardt (J)

Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, 10065, USA.

Dieter Egli (D)

Department of Pediatrics, Columbia University, New York, NY, 10032, USA.

Andrew G Clark (AG)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.
ORCID: 0000-0001-7159-8511

Amnon Koren (A)

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA. koren@cornell.edu.
ORCID: 0000-0002-7144-2602

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questionsmedicales.fr › Métabolisme › Acylation › Acétylation › The genetic architecture of DNA replication...
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