DNA replication and transcription programs respond to the same chromatin cues

Lubelsky, Yoav; Prinz, Joseph A.; DeNapoli, Leyna; Li, Yulong; Belsky, Jason A.; MacAlpine, David M.

doi:10.1101/gr.160010.113

Cited by 77 publications

(93 citation statements)

References 70 publications

(78 reference statements)

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“…Our results are in excellent accord with similar studies in Drosophila that mapped ORC2 binding sites with respect to numerous chromatin properties and transcription factor binding sites (4)(5)(6). Although there are some differences in the analyses performed and in the molecular interpretation, the overall similarities of results and conclusions are striking.…”

Section: Discussionsupporting

confidence: 88%

“…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)(5)(6). In mammals, the mechanism(s) through which ORC is localized and establishes a functional origin remains unclear.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 88%

mentioning

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 lower degree of compartmentalization and intermediate enrichment of transcription factors and histone marks in developmental domains may underlie their ability to switch between active and inactive epigenetic states more easily during the course of development. Indeed, a comparison of constitutive and developmental domains between two cell types in Drosophila revealed similar findings (Lubelsky et al 2014), and other studies have reported a similarity in nuclease sensitivity and origin density between developmental domains and constitutively late domains, regardless of their replication time (Besnard et al 2012;Takebayashi et al 2012).…”

Section: Wwwgenomeorgsupporting

confidence: 54%

Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program

et al. 2015

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Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established during early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chromatin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organization is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well compartmentalized than constitutive domains and display chromatin properties that distinguish them from early and late constitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during

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“…Early replication is globally associated with active gene expression in all multicellular organisms (Schübeler et al 2002(Schübeler et al , 2004MacAlpine et al 2004;Woodfine et al 2004;Huvet et al 2007;Desprat et al 2009;Hiratani et al 2009;Schwaiger et al 2009;Maric and Prioleau 2010;Lubelsky et al 2014), and developmentally regulated changes in RT are generally coordinated with transcriptional competence (Zhou et al 2002;Hiratani et al 2008Hiratani et al , 2010Desprat et al 2009;Schultz et al 2010;Yue et al 2014). However, causal relationships between RT and gene expression remain a long-standing puzzle.…”

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confidence: 99%

Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells

et al. 2015

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Duplication of the genome in mammalian cells occurs in a defined temporal order referred to as its replication-timing (RT) program. RT changes dynamically during development, regulated in units of 400-800 kb referred to as replication domains (RDs). Changes in RT are generally coordinated with transcriptional competence and changes in subnuclear position. We generated genome-wide RT profiles for 26 distinct human cell types, including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm, and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures) and confirmed global consolidation of the genome into larger synchronously replicating segments during differentiation. Surprisingly, transcriptome data revealed that the well-accepted correlation between early replication and transcriptional activity was restricted to RT-constitutive genes, whereas two-thirds of the genes that switched RT during differentiation were strongly expressed when late replicating in one or more cell types. Closer inspection revealed that transcription of this class of genes was frequently restricted to the lineage in which the RT switch occurred, but was induced prior to a late-to-early RT switch and/or down-regulated after an early-to-late RT switch. Analysis of transcriptional regulatory networks showed that this class of genes contains strong regulators of genes that were only expressed when early replicating. These results provide intriguing new insight into the complex relationship between transcription and RT regulation during human development.

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DNA replication and transcription programs respond to the same chromatin cues

Cited by 77 publications

References 70 publications

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

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

Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program

Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells

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