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Allele-specific Control Of Replication Timing And Genome Organization During Development

Title: Allele-specific Control Of Replication Timing And Genome Organization During Development.
Name(s): Rivera-Mulia, Juan Carlos, author
Dimond, Andrew, author
Vera, Daniel, author
Trevilla-Garcia, Claudia, author
Sasaki, Takayo, author
Zimmerman, Jared, author
Dupont, Catherine, author
Gribnau, Joost, author
Fraser, Peter, author
Gilbert, David M., author
Type of Resource: text
Genre: Journal Article
Journal Article
Date Issued: 2018-06-01
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: DNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus x castaneus mouse crosses and exploited the high single-nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (total nuclear RNA-seq), and chromatin accessibility (ATAC-seq). We also present HARP, a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of six different hybrid mESC clones with different genomes (C57BL/ 6,129 /sv, and CAST/ Ei), parental configurations, and gender revealed significant RT asynchrony between alleles across similar to 12% of the autosomal genome linked to subspecies genomes but not to parental origin, growth conditions, or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not as strongly with SNP density, gene expression, imprinting, or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types, including extraembryonic endoderm stem (XEN) cells, four male and female primary mouse embryonic fibroblasts (MEFs), and neural precursor cells (NPCs) differentiated in vitro from mESCs with opposite parental configurations. We found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs were largely lost in all differentiated cell types, accompanied by novel sites of allelic asynchrony at a considerably smaller proportion of the genome, suggesting that genome organization of homologs converges to similar folding patterns during cell fate commitment.
Identifier: FSU_libsubv1_wos_000436084800005 (IID), 10.1101/gr.232561.117 (DOI)
Keywords: mouse, dna-replication, embryonic stem-cells, in-situ hybridization, hi-c, stable units, acute lymphoblastic-leukemia, asynchronous replication, es cells, x-chromosome inactivation
Publication Note: The publisher’s version of record is available at
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Host Institution: FSU
Is Part Of: Genome Research.
Issue: iss. 6, vol. 28

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Rivera-Mulia, J. C., Dimond, A., Vera, D., Trevilla-Garcia, C., Sasaki, T., Zimmerman, J., … Gilbert, D. M. (2018). Allele-specific Control Of Replication Timing And Genome Organization During Development. Genome Research. Retrieved from