Unknown,Transcriptomics,Genomics,Proteomics

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Evolutionarily conserved replication timing profiles distinguish cell types and predict long range chromatin interaction

ABSTRACT: 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)

ORGANISM(S): Homo sapiens

SUBMITTER: Ichiro Hiratani

PROVIDER: E-GEOD-20027 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Abnormal replication timing has been observed in cancer but no study has comprehensively evaluated this misregulation. We generated genome-wide replication timing profiles for pediatric leukemias from 17 patients and 3 cell lines, as well as normal B and T cells. Non-leukemic EBV-transformed lymphoblastoid cell lines displayed highly stable replication timing profiles that were more similar to normal T cells than to leukemias. Leukemias were more similar to each other than to B and T cells but were considerably more heterogeneous than non-leukemic controls. Some differences were patient-specific while others were found in all leukemic samples, potentially representing early epigenetic events. Differences encompassed large segments of chromosomes and included genes implicated in other types of cancer. Remarkably, differences that distinguished leukemias aligned in register to the boundaries of developmentally regulated replication timing domains that distinguish normal cell types. Most changes did not coincide with copy number variation or translocations. However, many of the changes that were associated with translocations in some leukemias were also shared between all leukemic samples independent of the genetic lesion, suggesting that they precede and possibly predispose chromosomes to the translocation. Altogether, our results identify sites of abnormal developmental control of DNA replication in cancer that reveal the significance of replication timing boundaries to chromosome structure and function and support the replication domain model of replication timing regulation. They also open new avenues of investigation into the chromosomal basis of cancer and provide a potential novel source of epigenetic cancer biomarkers. Four karyotypically normal B-lymphoblastoid cell types with two replicates each, one peripheral T-lymphoblast replicate, 3 leukemic cell lines with 1-3 replicates each, 17 patient samples with 1-3 replicates each (total of 40 individual replicates)

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Evolutionarily conserved replication timing profiles distinguish cell types and predict long range chromatin interaction

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