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Genome-Wide Single-Molecule Analysis of Human Replication Kinetics

人类复制动力学的全基因组单分子分析

基本信息

批准号：
10221728
负责人：
NICHOLAS R RHIND
金额：
$ 48.81万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-23 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221728
关键词：
Address Affect B-Cell Development Benchmarking Biological Assay Biology Cancer Etiology Cell Differentiation process Cells Chromatin Chromosome Structures Chromosomes Companions Complex DNA DNA Replication Timing DNA biosynthesis DNA replication fork Data Development Diagnostic Epigenetic Process Erythropoiesis Evolution Fiber Fire - disasters Genetic Transcription Genome Genomic Instability Genomic approach Genomics Goals Heavy-Chain Immunoglobulins Hematopoietic Heterogeneity Human Human Genome IGH@ gene cluster Individual Kinetics Label Laboratories Lead Length Location Malignant Neoplasms Maps Mathematics Metabolism Mus Mutation Nature Noise Optics Pattern Physiologic pulse Prevention Regulation Replication Initiation Replication Origin Research Resolution S Phase Saccharomycetales Signal Transduction Site Speed Surveys Techniques Technology Testing Thymidine Time Transcriptional Regulation Variant Work analog beta Globin cell growth cellular development chromatin modification genome analysis genome-wide in vivo interest mathematical model new therapeutic target prevent programs single molecule single molecule real time sequencing stem cells tool

项目摘要

PROJECT SUMMARY The timing of DNA replication is a critical parameter of cellular growth. It correlates with patterns of transcriptional regulation, chromatin modification, chromosome structure and genome evolution. Furthermore, replication timing changes as cells differentiate, and disruption of replication timing correlates with genome instability, suggesting an intimate relation between replication timing and other important aspects of chromosome metabolism. A major impediment to understand the regulation of replication timing in the human genome has been the lack of robust assays for identifying the location and firing times of human replication origins. Current approaches suffer from low signal-to-noise ratios and poor concordance between independent laboratories. Moreover, ensemble techniques are unable to probe the coordination of origin firing, a subject significant interest in the field, because it has been proposed as a key factor in replication timing and efficiency. We propose to apply two new high-throughput single-molecule approaches that we have developed—Optical Replication Mapping and SMRT Repli-seq—to map replication origins and replication fork progression across the human genome. We will use replication profiles that we obtain to develop hypotheses about fundamental aspects of genome biology, such as such as how replication and transcription are coordinated, if the location of replication termination sites are regulated and how forks navigate difficult-to-replicate sequences. Successful completion of this work will elucidate the regulation of replication timing across the human genome, allow for the characterization of the sequence and epigenetic determinants for origin function, and provide robust origin maps and replication profiles for others to use. Moreover, dissemination of this technology will change the questions that biologists are able to ask about the regulation of DNA replication timing and its repercussions in diverse fields, such as development, chromatin biology, and epigenetics.

项目总结