Genome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication

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dc.contributor.authorWang, Weitao
dc.contributor.authorKlein, Kyle N.
dc.contributor.authorProesmans, Karel
dc.contributor.authorYang, Hongbo
dc.contributor.authorMarchal, Claire
dc.contributor.authorZhu, Xiaopeng
dc.contributor.authorBorrman, Tyler M.
dc.contributor.authorHastie, Alex
dc.contributor.authorWeng, Zhiping
dc.contributor.authorBechhoefer, John
dc.contributor.authorChen, Chun-Long
dc.contributor.authorGilbert, David M.
dc.contributor.authorRhind, Nicholas
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.date2022-08-11T08:08:27.000
dc.date.accessioned2022-08-23T15:55:54Z
dc.date.available2022-08-23T15:55:54Z
dc.date.issued2021-07-15
dc.date.submitted2021-08-10
dc.description.abstractThe heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation sites make mapping the location and timing of replication initiation in human cells difficult. To address this challenge, we have developed optical replication mapping (ORM), a high-throughput single-molecule approach, and used it to map early-initiation events in human cells. The single-molecule nature of our data and a total of > 2,500-fold coverage of the human genome on 27 million fibers averaging approximately 300 kb in length allow us to identify initiation sites and their firing probability with high confidence. We find that the distribution of human replication initiation is consistent with inefficient, stochastic activation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.
dc.identifier.citation<p>Wang W, Klein KN, Proesmans K, Yang H, Marchal C, Zhu X, Borrman T, Hastie A, Weng Z, Bechhoefer J, Chen CL, Gilbert DM, Rhind N. Genome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication. Mol Cell. 2021 Jul 15;81(14):2975-2988.e6. doi: 10.1016/j.molcel.2021.05.024. Epub 2021 Jun 21. PMID: 34157308; PMCID: PMC8286344. <a href="https://doi.org/10.1016/j.molcel.2021.05.024">Link to article on publisher's site</a></p>
dc.identifier.contextkey24268198
dc.identifier.doi10.1016/j.molcel.2021.05.024
dc.identifier.issn1097-2765 (Linking)
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/2064
dc.identifier.pmid34157308
dc.identifier.submissionpathfaculty_pubs/2064
dc.identifier.urihttps://hdl.handle.net/20.500.14038/29856
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34157308&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1016/j.molcel.2021.05.024
dc.source.issue14
dc.source.journaltitleMolecular cell
dc.source.pages2975-2988.e6
dc.source.volume81
dc.subjecteukaryotic replication kinetics
dc.subjectCell Biology
dc.subjectGenetics and Genomics
dc.subjectMolecular Biology
dc.titleGenome-wide mapping of human DNA replication by optical replication mapping supports a stochastic model of eukaryotic replication
dc.typeJournal Article
dspace.entity.typePublication
html.description.abstract<p>The heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation sites make mapping the location and timing of replication initiation in human cells difficult. To address this challenge, we have developed optical replication mapping (ORM), a high-throughput single-molecule approach, and used it to map early-initiation events in human cells. The single-molecule nature of our data and a total of > 2,500-fold coverage of the human genome on 27 million fibers averaging approximately 300 kb in length allow us to identify initiation sites and their firing probability with high confidence. We find that the distribution of human replication initiation is consistent with inefficient, stochastic activation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.</p>
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