The genetic architecture of DNA replication timing in human pluripotent stem cells.
Bracci, Alexa N
Hulke, Michelle L
Charvet, Christine J
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Ding, Q., Edwards, M. M., Wang, N., Zhu, X., Bracci, A. N., Hulke, M. L., Hu, Y., et al. (2021). The genetic architecture of DNA replication timing in human pluripotent stem cells.. Nature communications, 12 (1) https://doi.org/10.1038/s41467-021-27115-9
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.
Pluripotent Stem Cells, Humans, Histones, Transcription Factors, DNA Methylation, DNA Replication Timing, Gene Expression Regulation, Histone Code, Acetylation, Quantitative Trait Loci, Genome, Human, Female, Male, Datasets as Topic, Whole Genome Sequencing, Biological Variation, Population
Wellcome Trust (211221/Z/18/Z)
NIGMS NIH HHS (DP2 GM123495)
External DOI: https://doi.org/10.1038/s41467-021-27115-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332384
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/