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

Qiliang Ding, Matthew M. Edwards, Ning Wang, Xiang Zhu, Alexa N. Bracci, Michelle L. Hulke, Ya Hu, Yao Tong, Joyce Hsiao, Christine J. Charvet, Sulagna Ghosh, Robert E. Handsaker, Kevin Eggan, Florian T. Merkle, Jeannine Gerhardt, Dieter Egli, Andrew G. Clark and Amnon Koren ()
Additional contact information
Qiliang Ding: Cornell University
Matthew M. Edwards: Cornell University
Ning Wang: Columbia University
Xiang Zhu: Pennsylvania State University
Alexa N. Bracci: Cornell University
Michelle L. Hulke: Cornell University
Ya Hu: Cornell University
Yao Tong: Cornell University
Joyce Hsiao: University of Chicago
Christine J. Charvet: Cornell University
Sulagna Ghosh: Broad Institute of MIT and Harvard
Robert E. Handsaker: Broad Institute of MIT and Harvard
Kevin Eggan: Broad Institute of MIT and Harvard
Florian T. Merkle: University of Cambridge
Jeannine Gerhardt: Weill Cornell Medicine
Dieter Egli: Columbia University
Andrew G. Clark: Cornell University
Amnon Koren: Cornell University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27115-9

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DOI: 10.1038/s41467-021-27115-9

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