Abstract
BackgroundEukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status.ResultsTo identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types. Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions. Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. The first origin group consisted of about 40,000 regions that actively initiated replication in all cell types and preferentially colocalized with unmethylated CpGs and with the euchromatin markers, H3K4me3 and H3K9Ac. The second group included origins that were consistently active in cells of a single type or lineage and preferentially colocalized with the heterochromatin marker, H3K9me3. Shared origins replicated throughout the S-phase of the cell cycle, whereas cell-type-specific origins preferentially replicated during late S-phase.ConclusionsThese observations are in line with the hypothesis that differentiation-associated changes in chromatin and gene expression affect the activation of specific replication origins.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0067-3) contains supplementary material, which is available to authorized users.
Highlights
IntroductionEukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression
Eukaryotic genome duplication starts at discrete sequences that coordinate cell cycle progression, ensure genomic stability and modulate gene expression
Since cells of divergent lineages differed in the locations of replication initiation events [7, 9], we investigated whether cell-type-specific origins and shared origins were associated with distinct chromatin modifications
Summary
Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. In most somatic metazoan cells, chromosome replication starts at numerous, consistent initiation sites (“replication origins”) and advances in a precise temporal- and. [9, 14, 15], G-quadruplexes [7] and sequence asymmetry [11, 16] This sequence versatility suggests that primary DNA sequences are not the sole determinants of replication initiation events, and origin activity might depend on both genetic and epigenetic features. Pre-replication complexes are inactive when loaded onto chromatin; their activation requires the recruitment of additional proteins to form the CMG (Cdc, MCM and GINS) complex [22]. Pre-replication complexes within each cell are more numerous than actual replication initiation sites, and only a fraction of potential replication origins initiate replication during each cell cycle [2, 3, 25]
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