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Allele-specific control of replication timing and genome organization during development

Juan Carlos Rivera-Mulia, Andrew Dimond, Daniel Vera, Claudia Trevilla-Garcia, Takayo Sasaki, Jared Zimmerman, Catherine Dupont, Joost Gribnau, Peter Fraser, David M. Gilbert
doi: https://doi.org/10.1101/221762
Juan Carlos Rivera-Mulia
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
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Andrew Dimond
2The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
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Daniel Vera
3Center for Genomics and Personalized Medicine, Florida State University, Tallahassee, FL, USA
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Claudia Trevilla-Garcia
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
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Takayo Sasaki
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
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Jared Zimmerman
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
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Catherine Dupont
4Department of Reproduction and Development, Erasmus MC, University Medical Center, 3015GE Rotterdam, The Netherlands
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Joost Gribnau
4Department of Reproduction and Development, Erasmus MC, University Medical Center, 3015GE Rotterdam, The Netherlands
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Peter Fraser
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
2The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK
3Center for Genomics and Personalized Medicine, Florida State University, Tallahassee, FL, USA
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David M. Gilbert
1Department of Biological Science, Florida State University, Tallahassee, FL, 32306-4295, USA
3Center for Genomics and Personalized Medicine, Florida State University, Tallahassee, FL, USA
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Abstract

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 (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 6 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 ~12 % of the autosomal genome linked to sub-species 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 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, 4 male and female primary mouse embryonic fibroblasts (MEFs) and neural precursors (NPCs) differentiated in vitro from mESCs with opposite parental configurations. Surprisingly, we found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs was largely lost in all differentiated cell types, coordinated with a more uniform Hi-C compartment arrangement, suggesting that genome organization of homologues converges to similar folding patterns during cell fate commitment.

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Posted November 21, 2017.
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Allele-specific control of replication timing and genome organization during development
Juan Carlos Rivera-Mulia, Andrew Dimond, Daniel Vera, Claudia Trevilla-Garcia, Takayo Sasaki, Jared Zimmerman, Catherine Dupont, Joost Gribnau, Peter Fraser, David M. Gilbert
bioRxiv 221762; doi: https://doi.org/10.1101/221762
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Allele-specific control of replication timing and genome organization during development
Juan Carlos Rivera-Mulia, Andrew Dimond, Daniel Vera, Claudia Trevilla-Garcia, Takayo Sasaki, Jared Zimmerman, Catherine Dupont, Joost Gribnau, Peter Fraser, David M. Gilbert
bioRxiv 221762; doi: https://doi.org/10.1101/221762

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