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

TitleThe genetic architecture of DNA replication timing in human pluripotent stem cells.
Publication TypeJournal Article
Year of Publication2021
AuthorsDing Q, Edwards MM, Wang N, Zhu X, Bracci AN, Hulke ML, Hu Y, Tong Y, Hsiao J, Charvet CJ, Ghosh S, Handsaker RE, Eggan K, Merkle FT, Gerhardt J, Egli D, Clark AG, Koren A
JournalNat Commun
Date Published2021 11 19
KeywordsAcetylation, Biological Variation, Population, Datasets as Topic, DNA Methylation, DNA Replication Timing, Female, Gene Expression Regulation, Genome, Human, Histone Code, Histones, Humans, Male, Pluripotent Stem Cells, Quantitative Trait Loci, Transcription Factors, Whole Genome Sequencing

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.

Alternate JournalNat Commun
PubMed ID34799581
PubMed Central IDPMC8604924
Grant List / WT_ / Wellcome Trust / United Kingdom
DP2 GM123495 / GM / NIGMS NIH HHS / United States
MR/R015724/1 / MRC_ / Medical Research Council / United Kingdom
211221/Z/18/Z / WT_ / Wellcome Trust / United Kingdom