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

Nature Communications

Joyce Hsiao¹  Christine J. Charvet²  Alexa N. Bracci²  Michelle L. Hulke²  Amnon Koren²  Qiliang Ding²  Yao Tong²  Matthew M. Edwards²  Andrew G. Clark²  Ya Hu³  Ning Wang⁴  Dieter Egli⁴  Xiang Zhu⁵  Jeannine Gerhardt⁶  Robert E. Handsaker⁷  Sulagna Ghosh⁸  Kevin Eggan⁹  Florian T. Merkle^1,10 

[1] Department of Human Genetics, University of Chicago, 60637, Chicago, IL, USA;Department of Molecular Biology and Genetics, Cornell University, 14853, Ithaca, NY, USA;Department of Molecular Biology and Genetics, Cornell University, 14853, Ithaca, NY, USA;New York Genome Center, 10013, New York, NY, USA;Department of Pediatrics, Columbia University, 10032, New York, NY, USA;Department of Statistics, Pennsylvania State University, 16801, University Park, PA, USA;Huck Institutes of the Life Sciences, Pennsylvania State University, 16801, University Park, PA, USA;Department of Statistics, Stanford University, 94305, Stanford, CA, USA;Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, 10065, New York, NY, USA;Department of Obstetrics and Gynecology, Weill Cornell Medicine, 10065, New York, NY, USA;Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA;Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Genetics, Harvard Medical School, 02115, Boston, MA, USA;Department of Stem Cell and Regenerative Biology, Harvard University, 02138, Cambridge, MA, USA;Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 02142, Cambridge, MA, USA;Department of Stem Cell and Regenerative Biology, Harvard University, 02138, Cambridge, MA, USA;Howard Hughes Medical Institute, Harvard University, 02138, Cambridge, MA, USA;Wellcome Trust - Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom;

DOI  :  10.1038/s41467-021-27115-9

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY