Dataset Information

DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.

ABSTRACT: Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found in such regions, and that regions replicated early and late display distinct patterns of frequencies of SCNA boundaries, SCNA size and a preference for deletions over insertions. We show that long-range interaction and replication timing data alone can identify a significant proportion of SCNAs in an independent test data set. We propose a model for the generation of SCNAs in cancer, suggesting that data on spatial proximity of regions replicating at the same time can be used to predict the mutational landscapes of cancer genomes.

SUBMITTER: De S

PROVIDER: S-EPMC3923360 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.

De Subhajyoti S Michor Franziska F

Nature biotechnology 20111120 12

Somatic copy-number alterations (SCNA) are a hallmark of many cancer types, but the mechanistic basis underlying their genome-wide patterns remains incompletely understood. Here we integrate data on DNA replication timing, long-range interactions between genomic material, and 331,724 SCNAs from 2,792 cancer samples classified into 26 cancer types. We report that genomic regions of similar replication timing are clustered spatially in the nucleus, that the two boundaries of SCNAs tend to be found ...[more]

PMID: 22101487

Similar Datasets

Project description:To identify evolutionarily conserved features of replication timing and their relationship to epigenetic properties, we profiled replication timing genome-wide in four human embryonic stem cell (hESC) lines, hESC-derived neural precursor cells (NPCs), lymphoblastoid cells, and two human induced pluripotent stem cell lines (hiPSCs), and compared them with related mouse cell types. Results confirm the conservation of coordinately replicated megabase-sized "replication domains" punctuated by origin-suppressed regions. Differentiation-induced replication timing changes in both species occur in 400- to 800-kb units and are similarly coordinated with transcription changes. A surprising degree of cell-type-specific conservation in replication timing was observed across regions of conserved synteny, despite considerable species variation in the alignment of replication timing to isochore GC/LINE-1 content. Notably, hESC replication timing profiles were significantly more aligned to mouse epiblast-derived stem cells (mEpiSCs) than to mouse ESCs. Comparison with epigenetic marks revealed a signature of chromatin modifications at the boundaries of early replicating domains and a remarkably strong link between replication timing and spatial proximity of chromatin as measured by Hi-C analysis. Thus, early and late initiation of replication occurs in spatially separate nuclear compartments, but rarely within the intervening chromatin. Moreover, cell-type-specific conservation of the replication program implies conserved developmental changes in spatial organization of chromatin. Together, our results reveal evolutionarily conserved aspects of developmentally regulated replication programs in mammals, demonstrate the power of replication profiling to distinguish closely related cell types, and strongly support the hypothesis that replication timing domains are spatially compartmentalized structural and functional units of three-dimensional chromosomal architecture.

Project description:Extensive changes in replication timing occur during early mouse development, but their biological significance remains uncertain. To identify evolutionarily conserved features of replication timing and their relationships to epigenetic properties in humans, we profiled replication timing genome-wide in four human embryonic stem cell (hESC) lines, hESC-derived neural precursor cells (NPCs), lymphoblastoid cells, and two independently derived human induced pluripotent stem cell lines (hiPSCs). Results confirm the conservation of coordinately replicated megabase-sized units of chromosomes (replication domains) with stable cell type specific molecular boundaries that consolidate into larger replication domains during differentiation. Replication timing changes encompassed units of 400-800 kb and were coordinated with changes in transcription similar to mouse. Moreover, significant cell-type specific conservation of replication timing profiles was observed across regions of conserved synteny, despite significant species variation in the alignment of replication timing to isochore GC/LINE-1 content. Replication profiling also revealed a closer genome-wide epigenetic alignment of hESCs to mouse epiblast-derived stem cells (mEpiSCs) than to mouse ESCs. Finally, we identify a signature of chromatin modifications marking the boundaries of early replicating domains and a remarkably strong link between spatial proximity of chromatin as measured by Hi-C analysis and replication timing. Together, our results reveal evolutionarily conserved elements of the replication program in mammalian early development, demonstrate the power of replication profiling to identify important epigenetic distinctions between closely related stem cell populations (e.g. ESCs vs. EpiSCs), and strengthen the hypothesis that replication domains are structural and functional units of 3D chromosomal architecture. 8 cell types, with a total of 13 individual replicates (i.e. 5 in duplicates, 3 in single replicates)

Dataset Information

DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.

Publications

DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets