TY - JOUR
T1 - The genetic architecture of DNA replication timing in human pluripotent stem cells
AU - Ding, Qiliang
AU - Edwards, Matthew M.
AU - Wang, Ning
AU - Zhu, Xiang
AU - Bracci, Alexa N.
AU - Hulke, Michelle L.
AU - Hu, Ya
AU - Tong, Yao
AU - Hsiao, Joyce
AU - Charvet, Christine J.
AU - Ghosh, Sulagna
AU - Handsaker, Robert E.
AU - Eggan, Kevin
AU - Merkle, Florian T.
AU - Gerhardt, Jeannine
AU - Egli, Dieter
AU - Clark, Andrew G.
AU - Koren, Amnon
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85119485160&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119485160&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27115-9
DO - 10.1038/s41467-021-27115-9
M3 - Article
C2 - 34799581
AN - SCOPUS:85119485160
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6746
ER -