The genetic architecture of DNA replication timing in human pluripotent stem cells
| Autor: | Joyce Hsiao, Ya Hu, Ning Wang, Amnon Koren, Andrew G. Clark, Alexa N. Bracci, Kevin Eggan, Florian T. Merkle, Michelle L Hulke, Matthew M. Edwards, Christine J. Charvet, Sulagna Ghosh, Dieter Egli, Qiliang Ding, Xiang Zhu, Robert E. Handsaker, Jeannine Gerhardt, Yao Tong |
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| Přispěvatelé: | Edwards, Matthew M. [0000-0001-9134-4666], Zhu, Xiang [0000-0003-1134-6413], Handsaker, Robert E. [0000-0002-3128-3547], Eggan, Kevin [0000-0003-4436-8467], Merkle, Florian T. [0000-0002-8513-2998], Clark, Andrew G. [0000-0001-7159-8511], Koren, Amnon [0000-0002-7144-2602], Apollo - University of Cambridge Repository, Edwards, Matthew M [0000-0001-9134-4666], Handsaker, Robert E [0000-0002-3128-3547], Merkle, Florian T [0000-0002-8513-2998], Clark, Andrew G [0000-0001-7159-8511] |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Pluripotent Stem Cells Population genetics DNA Replication Timing Science Quantitative Trait Loci 45/43 Datasets as Topic General Physics and Astronomy 45/23 Computational biology DNA replication 631/208/457 General Biochemistry Genetics and Molecular Biology Histones 631/337/151 631/337/176 Humans Epigenetics Replication timing Genome Multidisciplinary Whole Genome Sequencing biology Genome Human article Acetylation General Chemistry DNA Methylation 631/208/726 Chromatin Histone Code Histone Biological Variation Population Gene Expression Regulation Replication Initiation biology.protein Female Human genome 45/100 Transcription Factors |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Funder: National Institute of Health (NIH) DP2-GM123495 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. |
| Databáze: | OpenAIRE |
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