H2A.Z facilitates licensing and activation of early replication origins

Long, Haizhen; Zhang, Liwei; Lv, Mengjie; Wen, Zengqi; Zhang, Wenhao; Chen, Xiu-Lan; Zhang, Peitao; Li, Tongqing; Chang, Luyuan; Jin, Caiwei; Wu, Guozhao; Wang, Xi; Yang, Fuquan; Pei, Jianfeng; Chen, Ping; Margueron, Raphaël; Deng, Haiteng; Zhu, Mingzhao; Li, Guohong

doi:10.1038/s41586-019-1877-9

Cited by 133 publications

(127 citation statements)

References 24 publications

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“…Comparing our IZs with various chromatin states from the ENCODE project (Bernstein et al, 2012;Ernst and Kellis, 2012), we find that they are enriched in enhancers and low activity intergenic regions and depleted in transcription units and polycomb-repressed chromatin ( Figure S4A). Examining specific histone modifications, our IZs are enriched in H2AZ, which has been implicated in ORC binding, and enhancer-specific modifications, such as H3K4me1 and H3K27ac, and they are depleted in, although adjacent to, transcriptionelongation-associated modifications, such as H3K79me2 and H3K36me2 (Figures 4 and S4B,D), in agreement with previous studies (Petryk et al, 2016;Long et al, 2020;Pourkarimi et al, 2016). Although metazoan ORC has only a weak affinity for AT-rich sequences in vitro (Vashee et al, 2003;De Carli et al, 2018) and no discernible sequence preference in vivo (Miotto et al, 2016), sequences that form G4 quadruplex structures have been proposed to correlate with initiation sites in vertebrate cells (Cayrou et al, 2015;Langley et al, 2016;Valton et al, 2014;Prorok et al, 2019).…”

Section: Characterization Of Initiation Zones Mapped By Ormsupporting

confidence: 92%

Genome-Wide Mapping of Human DNA Replication by Optical Replication Mapping Supports a Stochastic Model of Eukaryotic Replication

Wang

Klein

Proesmans

et al. 2020

Preprint

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DNA replication is regulated by the location and timing of replication initiation. Therefore, much effort has been invested in identifying and analyzing the sites of human replication initiation. However, the heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation site utilization in metazoans has made mapping the location and timing of replication initiation in human cells difficult. A potential solution to the problem of human replication mapping is single-molecule analysis. However, current approaches do not provide the throughput required for genome-wide experiments. To address this challenge, we have developed Optical Replication Mapping (ORM), a high-throughput single-molecule approach to map newly replicated DNA, and used it to map early initiation events in human cells. The single-molecule nature of our data, and a total of more than 2000-fold coverage of the human genome on 27 million fibers averaging ~300 kb in length, allow us to identify initiation sites and their firing probability with high confidence. In particular, for the first time, we are able to measure genome-wide the absolute efficiency of human replication initiation. We find that the distribution of human replication initiation is consistent with inefficient, stochastic initiation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. In particular, we find sites of human replication initiation are not confined to well-defined replication origins but are instead distributed across broad initiation zones consisting of many initiation sites. Furthermore, we find no correlation of initiation events between neighboring initiation zones. Although most early initiation events occur in early-replicating regions of the genome, a significant number occur in late replicating regions. The fact that initiation sites in typically late-replicating regions have some probability of firing in early S phase suggests that the major difference between initiation events in early and late replicating regions is their intrinsic probability of firing, as opposed to a qualitative difference in their firing-time distributions. Moreover, modeling of replication kinetics demonstrates that measuring the efficiency of initiation-zone firing in early S phase suffices to predict the average firing time of such initiation zones throughout S phase, further suggesting that the differences between the firing times of early and late initiation zones are quantitative, rather than qualitative. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.

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Section: Characterization Of Initiation Zones Mapped By Ormsupporting

confidence: 92%

Genome-Wide Mapping of Human DNA Replication by Optical Replication Mapping Supports a Stochastic Model of Eukaryotic Replication

Wang

Klein

Proesmans

et al. 2020

Preprint

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“…6 A,B). This observation provides support for the concept that some LADs from each category may be characterized as constitutive across multiple cell types, while others are more variable across cell types (Meuleman et al, 2013 (Long et al, 2020) , and poised RNA polymerase may provide an opportunity for even more in-depth analysis of this layered signature, possibly revealing even further sub-compartmentalization of peripheral heterochromatin beyond what we have described here.…”

Section: Cell Type Specificity In T1-lads T2-lads and Kddssupporting

confidence: 79%

An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype

Keough

Shah

Gjoni

et al. 2020

Preprint

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Three-dimensional genome organization, specifically organization of heterochromatin at the nuclear periphery, coordinates cell type-specific gene regulation. While defining various histone modifications and chromatin-associated proteins in multiple cell types has provided important insights into epigenetic regulation of gene expression and cellular identity, peripheral heterochromatin has not been mapped comprehensively and relatively few examples have emerged detailing the role of peripheral heterochromatin in cellular identity, cell fate choices, and/or organogenesis. In this study, we define nuclear peripheral heterochromatin organization signatures based on association with LAMIN B1 and/or dimethylation of lysine 9 on H3 (H3K9me2) across thirteen human cell types encompassing pluripotent stem cells, intermediate progenitors and differentiated cells from all three germ layers. Genomic analyses across this atlas reveal that lamin-associated chromatin is organized into at least two different compartments, defined by differences in genome coverage, chromatin accessibility, residence of transposable elements, replication timing domains, and gene complements. Our datasets reveal that only a small subset of lamin-associated chromatin domains are cell type invariant, underscoring the complexity of peripheral heterochromatin organization. Moreover, by integrating peripheral chromatin maps with transcriptional data, we find evidence of cooperative shifts between chromatin structure and gene expression associated with each cell type. This atlas of peripheral chromatin provides the largest resource to date for peripheral chromatin organization and a deeper appreciation for how this organization may impact the establishment and maintenance of cellular identity.

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“…Replication origins are also marked by epigenetic signatures, such as H2A.Z and H4k20me2/3, the presence of which is needed for ORC1 recruitment (Beck et al 2012;Long et al 2020;Kuo et al 2012). ORC binding is followed by the recruitment of cell division control protein 6 (CDC6), which stabilizes ORC binding (Speck and Stillman 2007), and CDC10-dependent transcript 1 (CDT1).…”

Section: Origin Licensing and Firing: A Two-step Processmentioning

confidence: 99%

The impact of transcription-mediated replication stress on genome instability and human disease

Gnan

Lin

Spagnuolo

et al. 2020

GENOME INSTAB. DIS.

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DNA replication is a vital process in all living organisms. At each cell division, > 30,000 replication origins are activated in a coordinated manner to ensure the duplication of > 6 billion base pairs of the human genome. During differentiation and development, this program must adapt to changes in chromatin organization and gene transcription: its deregulation can challenge genome stability, which is a leading cause of many diseases including cancers and neurological disorders. Over the past decade, great progress has been made to better understand the mechanisms of DNA replication regulation and how its deregulation challenges genome integrity and leads to human disease. Growing evidence shows that gene transcription has an essential role in shaping the landscape of genome replication, while it is also a major source of endogenous replication stress inducing genome instability. In this review, we discuss the current knowledge on the various mechanisms by which gene transcription can impact on DNA replication, leading to genome instability and human disease.

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H2A.Z facilitates licensing and activation of early replication origins

Cited by 133 publications

References 24 publications

Genome-Wide Mapping of Human DNA Replication by Optical Replication Mapping Supports a Stochastic Model of Eukaryotic Replication

Genome-Wide Mapping of Human DNA Replication by Optical Replication Mapping Supports a Stochastic Model of Eukaryotic Replication

An atlas of lamina-associated chromatin across twelve human cell types reveals an intermediate chromatin subtype

The impact of transcription-mediated replication stress on genome instability and human disease

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