Distinct epigenetic features of differentiation-regulated replication origins

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.

High Resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells

“…The sources of SNS-seq raw reads are stated in Table I. SNS-seq was aligned to hg38 using bowtie-2 and further processed according to (Smith et al, 2016). The source of OKseq signal bigwig files and called OKseq initiation zones for mESCs is stated in Table I.…”

High-resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells

“…The sources of SNS-seq raw reads are stated in Additional file 2 Table S2. SNS-seq was aligned to hg38 using bowtie-2 and further processed according to [54]. The source of OKseq signal bigwig files and called OKseq initiation zones for mESCs is stated in Additional file 2 Table S2.…”

Dynamic and Combinatorial Landscape of Histone Modifications during the Intraerythrocytic Developmental Cycle of the Malaria Parasite

“…As with transcriptional activation, elongation or repression, several lines of evidence suggest that histone PTMs play a role in coordinating DNA replication. Histone lysine methylation such as H4-K20me2 and H3-K79me2 or the euchromatin markers, H3-K4me3 and H3-K9ac, are often found at replication origins, while H3-K27me1 is also often detected at elongation sites 4, 5 . As a whole, dynamic changes of histone PTMs involved in replication and transcription correlate generally well with the genetic activity of the cell 6 .…”