Allele-specific control of replication timing and genome organization during development
2018
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 hybridmusculus × 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
asynchronybetween alleles across ∼12% of the autosomal genome linked to subspecies genomes but not to parental origin, growth conditions, or gender. RT
asynchronyin 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
asynchronyand allelic discordance in Hi-C compartments seen in mESCs were largely lost in all differentiated cell types, accompanied by novel sites of allelic
asynchronyat a considerably smaller proportion of the genome, suggesting that
genome organizationof homologs converges to similar folding patterns during cell fate commitment.
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