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The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle.

Mayra Furlan-Magaril, Masami Ando-Kuri, Rodrigo G Arzate-Mejía, Jörg Morf, Jonathan Cairns, Abraham Román-Figueroa, Luis Tenorio-Hernández, A César Poot-Hernández, Simon Andrews, Csilla Várnai, Boo Virk, Steven W Wingett, Peter Fraser,

<h4>Background</h4>Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized.<h4>Results</h4>Here we ... Read more >>

Genome Biol (Genome biology)
[2021, 22(1):162]

Cited: 1 time

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Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease.

Stephen Watt, Louella Vasquez, Klaudia Walter, Alice L Mann, Kousik Kundu, Lu Chen, Ying Sims, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo,

Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated ... Read more >>

Nat Commun (Nature communications)
[2021, 12(1):2298]

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Three-dimensional interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis

Ian Groves, Emma LA Drane, Marco Michalski, Jack Monahan, Cinzia Scarpini, Stephen Smith, Giovanni Bussotti, Csilla Várnai, Stefan Schoenfelder, Peter Fraser, Anton Enright, Nicholas Coleman,

Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of ... Read more >>

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High-resolution three-dimensional chromatin profiling of the Chinese hamster ovary cell genome.

Stephen Bevan, Stefan Schoenfelder, Robert J Young, Lin Zhang, Simon Andrews, Peter Fraser, Peter M O'Callaghan,

Chinese hamster ovary (CHO) cell lines are the pillars of a multibillion-dollar biopharmaceutical industry producing recombinant therapeutic proteins. The effects of local chromatin organization and epigenetic repression within these cell lines result in unpredictable and unstable transgene expression following random integration. Limited knowledge of the CHO genome and its higher ... Read more >>

Biotechnol Bioeng (Biotechnology and bioengineering)
[2021, 118(2):784-796]

Cited: 1 time

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Locus-specific induction of gene expression from heterochromatin loci during cellular senescence

Kosuke Tomimatsu, Dóra Bihary, Ioana Olan, Aled Parry, Stefan Schoenfelder, Adelyne Chan, Guy Slater, Yoko Ito, Peter Rugg-Gunn, Kristina Kirschner, Camino Bermejo-Rodriguez, Masako Narita, Tomomi Seko, Hiroyuki Kugoh, Ken Shiraishi, Koji Sayama, Hiroshi Kimura, Peter Fraser, Shamith Samarajiwa, Masashi Narita,

Cellular senescence is a fate-determined state, accompanied by reorganization of heterochromatin. While lineage-appropriate genes can be temporarily repressed through facultative heterochromatin, stable silencing of lineage-inappropriate genes often involves the constitutive heterochromatic mark, histone H3K9me3. The fate of these heterochromatic genes during the chromatin reorganization accompanying senescence is unclear. Here we ... Read more >>

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Highly interconnected enhancer communities control lineage-determining genes in human mesenchymal stem cells.

Jesper G S Madsen, Maria S Madsen, Alexander Rauch, Sofie Traynor, Elvira L Van Hauwaert, Anders K Haakonsson, Biola M Javierre, Mette Hyldahl, Peter Fraser, Susanne Mandrup,

Adipocyte differentiation is driven by waves of transcriptional regulators that reprogram the enhancer landscape and change the wiring of the promoter interactome. Here, we use high-throughput chromosome conformation enhancer capture to interrogate the role of enhancer-to-enhancer interactions during differentiation of human mesenchymal stem cells. We find that enhancers form an ... Read more >>

Nat Genet (Nature genetics)
[2020, 52(11):1227-1238]

Cited: 3 times

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Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.

Ioana Olan, Aled J Parry, Stefan Schoenfelder, Masako Narita, Yoko Ito, Adelyne S L Chan, Guy St C Slater, Dóra Bihary, Masashige Bando, Katsuhiko Shirahige, Hiroshi Kimura, Shamith A Samarajiwa, Peter Fraser, Masashi Narita,

Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):6049]

Cited: 3 times

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The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle

Masami Ando-Kuri, Rodrigo Arzate-Mejía, Jorg Morf, Jonathan Cairns, Cesar Poot-Hernández, Simon Andrews, Csilla Várnai, Boo Virk, Steven Wingett, Peter Fraser, Mayra Furlan-Magaril,

<h4>Summary</h4> Circadian gene expression is essential for organisms to adjust cellular responses and anticipate daily changes in the environment. In addition to its physiological importance, the clock circuit represents an ideal, temporally resolved, system to study transcription regulation. Here, we analysed changes in spatial mouse liver chromatin conformation using genome-wide ... Read more >>

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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis.

Jing Yang, Amanda McGovern, Paul Martin, Kate Duffus, Xiangyu Ge, Peyman Zarrineh, Andrew P Morris, Antony Adamson, Peter Fraser, Magnus Rattray, Stephen Eyre,

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ T cells ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):4402]

Cited: 6 times

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Active and repressed biosynthetic gene clusters have spatially distinct chromosome states.

Hans-Wilhelm Nützmann, Daniel Doerr, América Ramírez-Colmenero, Jesús Emiliano Sotelo-Fonseca, Eva Wegel, Marco Di Stefano, Steven W Wingett, Peter Fraser, Laurence Hurst, Selene L Fernandez-Valverde, Anne Osbourn,

While colocalization within a bacterial operon enables coexpression of the constituent genes, the mechanistic logic of clustering of nonhomologous monocistronic genes in eukaryotes is not immediately obvious. Biosynthetic gene clusters that encode pathways for specialized metabolites are an exception to the classical eukaryote rule of random gene location and provide ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2020, 117(24):13800-13809]

Cited: 9 times

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Parental-to-embryo switch of chromosome organization in early embryogenesis.

Samuel Collombet, Noémie Ranisavljevic, Takashi Nagano, Csilla Varnai, Tarak Shisode, Wing Leung, Tristan Piolot, Rafael Galupa, Maud Borensztein, Nicolas Servant, Peter Fraser, Katia Ancelin, Edith Heard,

Paternal and maternal epigenomes undergo marked changes after fertilization<sup>1</sup>. Recent epigenomic studies have revealed the unusual chromatin landscapes that are present in oocytes, sperm and early preimplantation embryos, including atypical patterns of histone modifications<sup>2-4</sup> and differences in chromosome organization and accessibility, both in gametes<sup>5-8</sup> and after fertilization<sup>5,8-10</sup>. However, these studies ... Read more >>

Nature (Nature)
[2020, 580(7801):142-146]

Cited: 14 times

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Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Michiel Thiecke, Gordana Wutz, Matthias Muhar, Wen Tang, Stephen Bevan, Valeriya Malysheva, Roman Stocsits, Tobias Neumann, Johannes Zuber, Peter Fraser, Stefan Schoenfelder, Jan-Michael Peters, Mikhail Spivakov,

It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics ... Read more >>

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Analysis of chromatin organization and gene expression in T cells identifies functional genes for rheumatoid arthritis

Jing Yang, Amanda McGovern, Paul Martin, Kate Duffus, Xiangyu Ge, Peyman Zarrineh, Andrew Morris, Antony Adamson, Peter Fraser, Magnus Rattray, Stephen Eyre,

Genome-wide association studies have identified genetic variation contributing to complex disease risk. However, assigning causal genes and mechanisms has been more challenging because disease-associated variants are often found in distal regulatory regions with cell-type specific behaviours. Here, we collect ATAC-seq, Hi-C, Capture Hi-C and nuclear RNA-seq data in stimulated CD4+ ... Read more >>

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ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL.

Gordana Wutz, Rene Ladurner, Brian Glenn St Hilaire, Roman R Stocsits, Kota Nagasaka, Benoit Pignard, Adrian Sanborn, Wen Tang, Csilla Várnai, Miroslav P Ivanov, Stefan Schoenfelder, Petra van der Lelij, Xingfan Huang, Gerhard Dürnberger, Elisabeth Roitinger, Karl Mechtler, Iain Finley Davidson, Peter Fraser, Erez Lieberman-Aiden, Jan-Michael Peters,

Eukaryotic genomes are folded into loops. It is thought that these are formed by cohesin complexes <i>via</i> extrusion, either until loop expansion is arrested by CTCF or until cohesin is removed from DNA by WAPL. Although WAPL limits cohesin's chromatin residence time to minutes, it has been reported that some ... Read more >>

Elife (eLife)
[2020, 9:]

Cited: 20 times

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ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL

Gordana Wutz, Rene Ladurner, Brian St. Hilaire, Roman Stocsits, Kota Nagasaka, Benoit Pignard, Adrian Sanborn, Wen Tang, Csilla Várnai, Miroslav Ivanov, Stefan Schoenfelder, Petra van der Lelij, Xingfan Huang, Gerhard Dürnberger, Elisabeth Roitinger, Karl Mechtler, Iain Davidson, Peter Fraser, Erez Lieberman Aiden, Jan-Michael Peters,

Eukaryotic genomes are folded into loops. It is thought that these are formed by cohesin complexes via extrusion, either until loop expansion is arrested by CTCF or until cohesin is removed from DNA by WAPL. Although WAPL limits cohesin’s chromatin residence time to minutes, it has been reported that some ... Read more >>

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An intergenic non-coding RNA promoter required for histone modifications in the human β-globin chromatin domain.

Emmanuel Debrand, Lyubomira Chakalova, Joanne Miles, Yan-Feng Dai, Beatriz Goyenechea, Sandra Dye, Cameron S Osborne, Alice Horton, Susanna Harju-Baker, Ryan C Pink, Daniel Caley, David R F Carter, Kenneth R Peterson, Peter Fraser,

Transcriptome analyses show a surprisingly large proportion of the mammalian genome is transcribed; much more than can be accounted for by genes and introns alone. Most of this transcription is non-coding in nature and arises from intergenic regions, often overlapping known protein-coding genes in sense or antisense orientation. The functional ... Read more >>

PLoS One (PloS one)
[2019, 14(8):e0217532]

Cited: 0 times

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Long-range enhancer-promoter contacts in gene expression control.

Stefan Schoenfelder, Peter Fraser,

Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer-promoter contacts and their functional dissection. ... Read more >>

Nat Rev Genet (Nature reviews. Genetics)
[2019, 20(8):437-455]

Cited: 132 times

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Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence

Ioana Olan, Aled Parry, Stefan Schoenfelder, Masako Narita, Yoko Ito, Adelyne S.L. Chan, Guy St.C. Slater, Dóra Bihary, Masashige Bando, Katsuhiko Shirahige, Hiroshi Kimura, Shamith Samarajiwa, Peter Fraser, Masashi Narita,

Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis 1,2 . Enhancer-promoter interactions play a key ... Read more >>

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Three-dimensional chromosome architecture and drug addiction.

Javed M Chitaman, Peter Fraser, Jian Feng,

Aberrant gene expression underlies drug addiction. Therefore, studying the regulation of gene expression in drug addiction may provide mechanistic insights into this disease, for which there are still only limited treatments. Recently, the three-dimensional (3D) organization of linear DNA in the nucleus has been recognized as having a major influence ... Read more >>

Curr Opin Neurobiol (Current opinion in neurobiology)
[2019, 59:137-145]

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Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes.

Irene Miguel-Escalada, Silvia Bonàs-Guarch, Inês Cebola, Joan Ponsa-Cobas, Julen Mendieta-Esteban, Goutham Atla, Biola M Javierre, Delphine M Y Rolando, Irene Farabella, Claire C Morgan, Javier García-Hurtado, Anthony Beucher, Ignasi Morán, Lorenzo Pasquali, Mireia Ramos-Rodríguez, Emil V R Appel, Allan Linneberg, Anette P Gjesing, Daniel R Witte, Oluf Pedersen, Niels Grarup, Philippe Ravassard, David Torrents, Josep M Mercader, Lorenzo Piemonti, Thierry Berney, Eelco J P de Koning, Julie Kerr-Conte, François Pattou, Iryna O Fedko, Leif Groop, Inga Prokopenko, Torben Hansen, Marc A Marti-Renom, Peter Fraser, Jorge Ferrer,

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, ... Read more >>

Nat Genet (Nature genetics)
[2019, 51(7):1137-1148]

Cited: 48 times

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An intergenic non-coding RNA promoter required for histone modifications in the human β-globin chromatin domain

Emmanuel Debrand, Lyubomira Chakalova, Joanne Miles, Yan-Feng Dai, Beatriz Goyenechea, Sandra Dye, Cameron Osborne, Alice Horton, Susanna Harju-Baker, Ryan Pink, Daniel Caley, David Carter, Kenneth Peterson, Peter Fraser,

Transcriptome analyses show a surprisingly large proportion of the mammalian genome is transcribed; much more than can be accounted for by genes and introns alone. Most of this transcription is non-coding in nature and arises from intergenic regions, often overlapping known protein-coding genes in sense or antisense orientation. The functional ... Read more >>

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Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

Stephen Watt, Louella Vasquez, Klaudia Walter, Alice Mann, Kousik Kundu, Lu Chen, Ying Yan, Simone Ecker, Frances Burden, Samantha Farrow, Ben Farr, Valentina Iotchkova, Heather Elding, Daniel Mead, Manuel Tardaguila, Hannes Ponstingl, David Richardson, Avik Datta, Paul Flicek, Laura Clarke, Kate Downes, Tomi Pastinen, Peter Fraser, Mattia Frontini, Biola-Maria Javierre, Mikhail Spivakov, Nicole Soranzo,

Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity 1 , and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases 2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we ... Read more >>

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Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.

Jiao Sima, Abhijit Chakraborty, Vishnu Dileep, Marco Michalski, Kyle N Klein, Nicolas P Holcomb, Jesse L Turner, Michelle T Paulsen, Juan Carlos Rivera-Mulia, Claudia Trevilla-Garcia, Daniel A Bartlett, Peiyao A Zhao, Brian K Washburn, Elphège P Nora, Katerina Kraft, Stefan Mundlos, Benoit G Bruneau, Mats Ljungman, Peter Fraser, Ferhat Ay, David M Gilbert,

The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion ... Read more >>

Cell (Cell)
[2019, 176(4):816-830.e18]

Cited: 31 times

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Challenges and guidelines toward 4D nucleome data and model standards.

Marc A Marti-Renom, Genevieve Almouzni, Wendy A Bickmore, Kerstin Bystricky, Giacomo Cavalli, Peter Fraser, Susan M Gasser, Luca Giorgetti, Edith Heard, Mario Nicodemi, Marcelo Nollmann, Modesto Orozco, Ana Pombo, Maria-Elena Torres-Padilla,

Due to recent advances in experimental and theoretical approaches, the dynamic three-dimensional organization (3D) of the nucleus has become a very active area of research in life sciences. We now understand that the linear genome is folded in ways that may modulate how genes are expressed during the basic functioning ... Read more >>

Nat Genet (Nature genetics)
[2018, 50(10):1352-1358]

Cited: 14 times

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Author Correction: Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks.

Mun-Kit Choy, Biola M Javierre, Simon G Williams, Stephanie L Baross, Yingjuan Liu, Steven W Wingett, Artur Akbarov, Chris Wallace, Paula Freire-Pritchett, Peter J Rugg-Gunn, Mikhail Spivakov, Peter Fraser, Bernard D Keavney,

In the original version of the Article, the gene symbol for tissue factor pathway inhibitor was inadvertently given as 'TFP1' instead of 'TFPI'. This has now been corrected in both the PDF and HTML versions of the Article. ... Read more >>

Nat Commun (Nature communications)
[2018, 9(1):4792]

Cited: 1 time

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