RT Journal Article
SR Electronic
T1 The Genetic Architecture of DNA Replication Timing in Human Pluripotent Stem Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.05.08.085324
DO 10.1101/2020.05.08.085324
A1 Qiliang Ding
A1 Matthew M. Edwards
A1 Michelle L. Hulke
A1 Alexa N. Bracci
A1 Ya Hu
A1 Yao Tong
A1 Xiang Zhu
A1 Joyce Hsiao
A1 Christine J. Charvet
A1 Sulagna Ghosh
A1 Robert E. Handsaker
A1 Kevin Eggan
A1 Florian T. Merkle
A1 Jeannine Gerhardt
A1 Dieter Egli
A1 Andrew G. Clark
A1 Amnon Koren
YR 2020
UL http://biorxiv.org/content/early/2020/05/10/2020.05.08.085324.abstract
AB DNA replication follows a strict spatiotemporal program that intersects with chromatin structure and gene regulation. However, the genetic basis of the mammalian DNA replication timing program is poorly understood1–3. To systematically identify genetic regulators of DNA replication timing, we exploited inter-individual variation in 457 human pluripotent stem cell lines 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 (rtQTLs4) – base-pair-resolution sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, to affect replication timing. Analysis of rtQTL locations reveals a histone code for replication initiation, composed of bivalent histone H3 trimethylation marks on a background of histone hyperacetylation. The H3 trimethylation marks are individually repressive yet synergize to promote early replication. We further identify novel positive and negative regulators of DNA replication timing, the former comprised of pluripotency-related transcription factors while the latter involve boundary elements. Human replication timing is controlled by a multi-layered mechanism that operates on target DNA sequences, is composed of dozens of effectors working combinatorially, and follows principles analogous to transcription regulation: a histone code, activators and repressors, and a promoter-enhancer logic.Competing Interest StatementThe authors have declared no competing interest.