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

Nat Commun. 2021 Nov 19;12(1):6746. doi: 10.1038/s41467-021-27115-9.

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.

Publication types

  • 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.

MeSH terms

  • 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

Substances

  • Histones
  • Transcription Factors