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. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. 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. 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. To 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. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status. These observations are consistent with a model, suggesting that RepID facilitates replication initiation at a distinct group of human replication origins.Įukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. RepID-depleted murine embryonic fibroblasts exhibit abnormal replication fork progression and fewer replication-initiation events. At HBB, RepID is involved in an interaction between the replication origin (Rep-P) and the locus control region. RepID is required for initiation of DNA replication from RepID-bound replication origins, including the origin at the human beta-globin (HBB) locus. A large fraction of RepID-binding sites share a common G-rich motif and exhibit elevated replication initiation. Here we identify a replication-initiation determinant (RepID) protein that binds a subset of replication-initiation sites. Mammalian chromosome replication starts from distinct sites however, the principles governing initiation site selection are unclear because proteins essential for DNA replication do not exhibit sequence-specific DNA binding. We also discuss evidence that it is possible to induce a similar structural postmitotic state in nonneural cell types as a practical strategy for stopping or reducing the progression of cancer. Here we discuss the evidence that the postmitotic state of neurons has a structural basis on the high stability of their nuclear higher order structure that performs like an absolute tumor suppressor. This fact suggests that in the real nonexperimental setting mutations per se are not enough for inducing carcinogenesis but also that the postmitotic state of neurons is not genetically controlled or determined, otherwise there should be reports of spontaneously transformed neurons. However, the evidence also shows that mutations and gross chromosomal anomalies are common in functional neurons that nevertheless do not become neoplastic. The dominant paradigm on cancer understands this problem as a disease caused by mutations in cellular genes that result in unrestrained cell proliferation and eventually in tissue invasion and metastasis. In particular, the evidence indicates that neurons are absolutely resistant to cancer and this is commonly explained on the basis of the known postmitotic state of neurons. However, the incidence of cancer is unevenly distributed among tissues and cell types. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development.Ĭancer is a major concern for contemporary societies. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Recently, it was shown that histone H1 imposes a non-permissive chromatin configuration preventing replication origin assembly on somatic nuclei. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing replication assembly origins at all available sites. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid-blastula transition (MBT) when cell cycle length increases and gene transcription starts. This guarantees rapid genome duplication coordinated with fast cell divisions. During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins.
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