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

Author

Listed:
  • Qiliang Ding

    (Cornell University)

  • Matthew M. Edwards

    (Cornell University)

  • Ning Wang

    (Columbia University)

  • Xiang Zhu

    (Pennsylvania State University
    Pennsylvania State University
    Stanford University)

  • Alexa N. Bracci

    (Cornell University)

  • Michelle L. Hulke

    (Cornell University)

  • Ya Hu

    (Cornell University
    New York Genome Center)

  • Yao Tong

    (Cornell University)

  • Joyce Hsiao

    (University of Chicago)

  • Christine J. Charvet

    (Cornell University)

  • Sulagna Ghosh

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Harvard University)

  • Robert E. Handsaker

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Kevin Eggan

    (Broad Institute of MIT and Harvard
    Harvard University
    Harvard University)

  • Florian T. Merkle

    (University of Cambridge)

  • Jeannine Gerhardt

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Dieter Egli

    (Columbia University)

  • Andrew G. Clark

    (Cornell University)

  • Amnon Koren

    (Cornell University)

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.

Suggested Citation

  • Qiliang Ding & Matthew M. Edwards & Ning Wang & Xiang Zhu & Alexa N. Bracci & Michelle L. Hulke & Ya Hu & Yao Tong & Joyce Hsiao & Christine J. Charvet & Sulagna Ghosh & Robert E. Handsaker & Kevin Eg, 2021. "The genetic architecture of DNA replication timing in human pluripotent stem cells," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27115-9
    DOI: 10.1038/s41467-021-27115-9
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    Cited by:

    1. Dashiell J. Massey & Amnon Koren, 2022. "High-throughput analysis of single human cells reveals the complex nature of DNA replication timing control," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Michael B. Heskett & Athanasios E. Vouzas & Leslie G. Smith & Phillip A. Yates & Christopher Boniface & Eric E. Bouhassira & Paul T. Spellman & David M. Gilbert & Mathew J. Thayer, 2022. "Epigenetic control of chromosome-associated lncRNA genes essential for replication and stability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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