Genome-wide depletion of replication initiation events in highly transcribed regions

Martin, Melvenia M.; Ryan, Michaël; Kim, Ryang Guk; Zakas, Anna; Fu, Haiqing; Lin, Chii M.; Reinhold, William C.; Davis, Sean; Bilke, Sven; Liu, Hongfang; Doroshow, James H.; Reimers, Mark; Valenzuela, Manuel S.; Pommier, ﻿Yves; Meltzer, Paul S.; Aladjem, Mirit I.

doi:10.1101/gr.124644.111

Cited by 119 publications

(233 citation statements)

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“…But, in contrast to ORC-binding profiles in Drosophila (MacAlpine et al, 2010), gene bodies rather than promoter regions of active genes were enriched with initiation events (Cayrou et al, 2011). Furthermore, both studies found that initiation events were underrepresented at the actual transcription start sites (TSS) and that CpG-rich sequences were enriched with initiation events (Cayrou et al, 2011;Martin et al, 2011). …”

Section: Potential Origins Of Replication Are Subject To Developmentamentioning

confidence: 96%

“…More recently, two genome-scale studies have used nascentstrand analysis (see Box 2) to map replication origins in two human cancer cell lines, three mouse cell lines and a Drosophila cell line (Cayrou et al, 2011;Martin et al, 2011). In all lines, the majority of initiation events were associated with active transcription units.…”

Section: Potential Origins Of Replication Are Subject To Developmentamentioning

confidence: 99%

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Regulation of DNA replication during development

2012

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SummaryAs development unfolds, DNA replication is not only coordinated with cell proliferation, but is regulated uniquely in specific cell types and organs. This differential regulation of DNA synthesis requires crosstalk between DNA replication and differentiation. This dynamic aspect of DNA replication is highlighted by the finding that the distribution of replication origins varies between differentiated cell types and changes with differentiation. Moreover, differential DNA replication in some cell types can lead to increases or decreases in gene copy number along chromosomes. This review highlights the recent advances and technologies that have provided us with new insights into the developmental regulation of DNA replication.

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Section: Potential Origins Of Replication Are Subject To Developmentamentioning

confidence: 96%

Section: Potential Origins Of Replication Are Subject To Developmentamentioning

confidence: 99%

Regulation of DNA replication during development

2012

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“…DNA combing technology, replication timing analysis, short nascent strand (SNS) enrichment, and bubble trapping approaches suggest that DNA replication initiation sites are enriched in CpG-rich regions, open chromatin domains, and transcriptional regulatory elements (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, these methods lack the necessary resolution to investigate important relationships of ORC binding with other features of the genome.…”

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confidence: 99%

Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers

Miotto

Struhl

2016

Proc. Natl. Acad. Sci. U.S.A.

176

216

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The origin recognition complex (ORC) binds sites from which DNA replication is initiated. We address ORC binding selectivity in vivo by mapping ∼52,000 ORC2 binding sites throughout the human genome. The ORC binding profile is broader than those of sequence-specific transcription factors, suggesting that ORC is not bound or recruited to specific DNA sequences. Instead, ORC binds nonspecifically to open (DNase I-hypersensitive) regions containing active chromatin marks such as H3 acetylation and H3K4 methylation. ORC sites in early and late replicating regions have similar properties, but there are far more ORC sites in early replicating regions. This suggests that replication timing is due primarily to ORC density and stochastic firing of origins. Computational simulation of stochastic firing from identified ORC sites is in accord with replication timing data. Large genomic regions with a paucity of ORC sites are strongly associated with common fragile sites and recurrent deletions in cancers. We suggest that replication origins, replication timing, and replication-dependent chromosome breaks are determined primarily by the genomic distribution of activator proteins at enhancers and promoters. These activators recruit nucleosome-modifying complexes to create the appropriate chromatin structure that allows ORC binding and subsequent origin firing.DNA replication | replication origins | chromatin | replication timing | ORC R eplication origins are established by the assembly of the prereplication complex at discrete sites of the genome. The first step of this process involves binding of the highly conserved six-subunit origin recognition complex (ORC), which serves as a loading platform for the subsequent assembly of helicases, DNA polymerases, and cofactors required for DNA synthesis (1, 2). In the yeast Saccharomyces cerevisiae, ORC binds DNA in an ATP-dependent manner and recognizes a specific DNA sequence (3). In Drosophila, ORC localizes to regions of open chromatin with contributions from activating histone modifications, DNA sequence, DNA binding proteins, and nucleosome remodelers (4-6). In mammals, the mechanism(s) through which ORC is localized and establishes a functional origin remains unclear.A great deal of effort and a variety of experimental approaches have been devoted to describing the nature and position of replication origins in mammalian genomes. DNA combing technology, replication timing analysis, short nascent strand (SNS) enrichment, and bubble trapping approaches suggest that DNA replication initiation sites are enriched in CpG-rich regions, open chromatin domains, and transcriptional regulatory elements (7-17). However, these methods lack the necessary resolution to investigate important relationships of ORC binding with other features of the genome. In addition, the divergence in protocols and bioinformatic pipelines between laboratories has led to some controversial and nonreproducible observations. Finally, these studies assume that the identified replication initiation sites are compa...

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“…In contrast, progress in elucidating the chromatin-mediated control of replication origin usage and efficiency as well as of the maintenance of the spatio-temporal replication program in higher eukaryotes has been rather slow (Berezney et al 2000;Bogan et al 2000;Gilbert 2001Gilbert , 2010Méchali 2001Méchali , 2010Bell & Dutta 2002;McNairn & Gilbert 2003;Aladjem 2007;Courbet et al 2008;Hamlin et al 2008). Only very recently nascent DNA strands synthesized at origins were purified by various methods to map replication origins genome-wide in mouse (Sequeira-Mendes et al 2009;Cayrou et al 2011) and human (Lucas et al 2007;Cadoret et al 2008;Karnani et al 2010;Martin et al 2011;Mesner et al 2011;Valenzuela et al 2011). The set of replication origins identified so far are strongly associated with annotated promoters and seem to be enriched in transcription factor binding sites (Cadoret et al 2008;Karnani et al 2010;Besnard et al 2012) and in CpG islands (Cadoret et al 2008;Sequeira-Mendes et al 2009;Cayrou et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of the human genome: coherence between promoter activity and large-scale chromatin environment

Julienne

Zoufir

Audit

et al. 2013

Frontiers in Life Science

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Increasing knowledge of chromatin structure in various cell types raises the challenge of deciphering the contribution of epigenetic modifications to the regulation of nuclear functions in mammals. In a recent study, we have analysed the genomewide distributions of thirteen epigenetic marks in the human cell line K562 at 100 kb resolution of Mean Replication Timing (MRT) data. Using classical clustering techniques, we have shown that the combinatorial complexity of these epigenetic data can be reduced to four predominant chromatin states that replicate at different periods of the S-phase. C1 is an early replicating transcriptionally active euchromatin state, C2 a mid-S repressive type of chromatin associated with Polycomb complexes, C3 a silent chromatin with lack of chromatin marks that replicates later than C2 but before C4, a HP1-associated heterochromatin state that replicates at the end of S-phase. These four chromatin states display remarkable similarities with those recently reported in fly, worm and plants at higher ∼ 1 kb resolution of gene expression data. Here, we extend our integrative analysis of epigenetic data in the K562 human cell line to this smaller scale by focusing on gene promoters (±3 kb around transcription start sites). We show that these promoters can similarly be classified into four main chromatin states: P1 regroups all the marks of transcriptionally active chromatin and corresponds to CpG rich promoters of highly expressed genes; P2 is notably associated with the histone modification H3K27me3 that is the mark of a polycomb repressed chromatin state; P3 corresponds to promoters that are not enriched for any available marks as the signature of a 'null' or 'black' silent heterochromatin state and P4 characterizes the few gene promoters that contain only the constitutive heterochromatin histone modification H3K9me3. When investigating the coherence between promoter activity (P1, P2, P3 or P4) and the large-scale chromatin environment (C1, C2, C3 or C4), we find that the higher the gene density in a considered 100 kb-window, the higher (resp. the lower) the probability of a P1 active promoter (resp. silent P2, P3 and P4 promoters) to be surrounded by an open euchromatin C1 (resp. facultative C2, black C3 or HP1-associated C4 heterochromatin) environment. From large to small scales, it is mainly C4 and to a lesser extent C3 heterochromatin environments both corresponding to gene poor regions, that strongly conditions promoters to belong to the inactive P3 and P4 classes. If C1 (resp. C2) environment surrounds a majority of corresponding active P1 (resp. P2) promoters, it also contains a non-negligible proportion of inactive P2 and P3 (resp. active P1 and inactive P3) promoters. When further investigating the large-scale organization of human genes with respect to 'master' replication origins that were shown to border megabase-sized U-shaped MRT domains, we reveal some significant enrichment of highly expressed P1 genes in a closed neighbourhood of these early initiation zones consistently...

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Genome-wide depletion of replication initiation events in highly transcribed regions

Cited by 119 publications

References 53 publications

Regulation of DNA replication during development

Regulation of DNA replication during development

Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers

Epigenetic regulation of the human genome: coherence between promoter activity and large-scale chromatin environment

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