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Identification of Replication Timing Domains Using DNN-HMM

ABSTRACT: Purpose: Sixteen GSM Samples from GSE34399 was used to identify four different types of replication timing domains. Methods: 1. Chromosome 1 of Bj_Rep1 was manually annotated. 2. We developed a new supervised method called DNN-HMM (Deep Neural Network-Hidden Markov Model), and used the manual annotation as the training set to learn a model. 3. The model learnt in Step 2 was used to divide the un-annotated Repli-seq datas into four different replication domains (early replication domain, down transition zone, late replication domain, up transition zone). Result: We used DNN-HMM to identify four different replication timing domains respectively in fifteen cell lines. The accuracy of identification was about 87%, and the overlapping percentage of two independent replicates of Bj cell line was about 83%. Data File Formats :(bed) chrom - The name of the chromosome chromStart - The starting position of the feature in the chromosome chromEnd - The ending position of the feature in the chromosome category - The domain identified (denoted by: ERD, short for early replication domain; DTZ, short for down transition zone; LRD, short for late replication domain; UTZ, short for up transition zone)

ORGANISM(S): Homo sapiens

PROVIDER: GSE53984 | GEO | 2015/05/25

SECONDARY ACCESSION(S): PRJNA234285

REPOSITORIES: GEO

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Project description:Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains;), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale.Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.

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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Identification of Replication Timing Domains Using DNN-HMM

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