The genetic architecture of DNA replication timing in human pluripotent stem cells. Academic Article uri icon

Overview

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 date

  • November 19, 2021

Research

keywords

  • DNA Replication Timing
  • Genome, Human
  • Pluripotent Stem Cells

Identity

PubMed Central ID

  • PMC8604924

Scopus Document Identifier

  • 85119485160

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-27115-9

PubMed ID

  • 34799581

Additional Document Info

volume

  • 12

issue

  • 1