Publications
52 results found
Worssam MD, Lambert J, Oc S, et al., 2023, Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease, CARDIOVASCULAR RESEARCH, Vol: 119, Pages: 1279-1294, ISSN: 0008-6363
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- Citations: 5
Ray-Jones H, Spivakov M, 2022, Brief encounters: The relationship between enhancer proximity and gene expression, DEVELOPMENTAL CELL, Vol: 57, Pages: 1439-1441, ISSN: 1534-5807
Frantzesko A, Malysheva V, Shi C, et al., 2022, IDENTIFICATION OF CAUSAL GENES AND MECHANISMS BY WHICH GENETIC VARIATION MEDIATES JUVENILE IDIOPATHIC ARTHRITIS SUSCEPTIBILITY USING FUNCTIONAL GENOMICS AND CRISPR-CAS9, EULAR European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 146-146, ISSN: 0003-4967
Thiecke M, Yang E, Burren OS, et al., 2021, Prioritisation of candidate genes underpinning COVID-19 host genetic traits based on high-resolution 3D chromosomal topology, Frontiers in Genetics, Vol: 12, Pages: 1-10, ISSN: 1664-8021
Genetic variants showing associations with specific biological traits and diseases detected by genome-wide association studies (GWAS) commonly map to non-coding DNA regulatory regions. Many of these regions are located considerable distances away from the genes they regulate and come into their proximity through 3D chromosomal interactions. We previously developed COGS, a statistical pipeline for linking GWAS variants with their putative target genes based on 3D chromosomal interaction data arising from high-resolution assays such as Promoter Capture Hi-C (PCHi-C). Here, we applied COGS to COVID-19 Host Genetic Consortium (HGI) GWAS meta-analysis data on COVID-19 susceptibility and severity using our previously generated PCHi-C results in 17 human primary cell types and SARS-CoV-2-infected lung carcinoma cells. We prioritise 251 genes putatively associated with these traits,including 16 out of 47 genes highlighted by the GWAS meta-analysis authors. The prioritised genes are expressed in a broad arrayof tissues, including, but not limited to, blood and brain cells, and are enriched for genes involved in the inflammatory response to viral infection. Our prioritised genes and pathways, in conjunction with results from other prioritisation approaches and targeted validation experiments, will aid in the understanding of COVID-19 pathology, paving the way for novel treatments.
Ray-Jones H, Spivakov M, 2021, Transcriptional enhancers and their communication with gene promoters, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 78, Pages: 6453-6485, ISSN: 1420-682X
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- Citations: 14
Freire-Pritchett P, Ray-Jones H, Della Rosa M, et al., 2021, Detecting chromosomal interactions in Capture Hi-C data with CHiCAGO and companion tools, NATURE PROTOCOLS, Vol: 16, Pages: 4144-+, ISSN: 1754-2189
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- Citations: 10
Ho JSY, Mok BW-Y, Campisi L, et al., 2021, TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation, CELL, Vol: 184, Pages: 2618-+, ISSN: 0092-8674
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- Citations: 43
Watt S, Vasquez L, Walter K, et al., 2021, Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility, bioRxiv
Thiecke MJ, Wutz G, Muhar M, et al., 2020, Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers, CELL REPORTS, Vol: 32, ISSN: 2211-1247
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- Citations: 75
Della Rosa M, Spivakov M, 2020, Silencers in the spotlight, NATURE GENETICS, Vol: 52, Pages: 244-245, ISSN: 1061-4036
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- Citations: 7
Cairns J, Orchard WR, Malysheva V, et al., 2019, Chicdiff: a computational pipeline for detecting differential chromosomal interactions in Capture Hi-C data, BIOINFORMATICS, Vol: 35, Pages: 4764-4766, ISSN: 1367-4803
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- Citations: 9
Mitchelmore J, Grinberg N, Wallace C, et al., 2019, Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters
Malysheva V, Mendoza-Parra MA, Blum M, et al., 2019, Gene regulatory network reconstruction incorporating 3D chromosomal architecture reveals key transcription factors and DNA elements driving neural lineage commitment, Publisher: bioRxiv
Dobnikar L, Taylor AL, Chappell J, et al., 2018, Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels (vol 9, 4567, 2018), NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
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- Citations: 7
Dobnikar L, Taylor AL, Chappell J, et al., 2018, Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels, NATURE COMMUNICATIONS, Vol: 9
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- Citations: 158
Koohy H, Bolland DJ, Matheson LS, et al., 2018, Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells, Genome Biology, Vol: 19, ISSN: 1474-7596
BackgroundAging is characterized by loss of function of the adaptive immune system, but the underlying causes are poorly understood. To assess the molecular effects of aging on B cell development, we profiled gene expression and chromatin features genome-wide, including histone modifications and chromosome conformation, in bone marrow pro-B and pre-B cells from young and aged mice.ResultsOur analysis reveals that the expression levels of most genes are generally preserved in B cell precursors isolated from aged compared with young mice. Nonetheless, age-specific expression changes are observed at numerous genes, including microRNA encoding genes. Importantly, these changes are underpinned by multi-layered alterations in chromatin structure, including chromatin accessibility, histone modifications, long-range promoter interactions, and nuclear compartmentalization. Previous work has shown that differentiation is linked to changes in promoter-regulatory element interactions. We find that aging in B cell precursors is accompanied by rewiring of such interactions. We identify transcriptional downregulation of components of the insulin-like growth factor signaling pathway, in particular downregulation of Irs1 and upregulation of Let-7 microRNA expression, as a signature of the aged phenotype. These changes in expression are associated with specific alterations in H3K27me3 occupancy, suggesting that Polycomb-mediated repression plays a role in precursor B cell aging.ConclusionsChanges in chromatin and 3D genome organization play an important role in shaping the altered gene expression profile of aged precursor B cells. Components of the insulin-like growth factor signaling pathways are key targets of epigenetic regulation in aging in bone marrow B cell precursors.
Choy M-K, Javierre BM, Williams SG, et al., 2018, Promoter interactome of human embryonic stem cell-derived cardiomyocytes connects GWAS regions to cardiac gene networks, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723
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- Citations: 34
Rubin AJ, Barajas BC, Furlan-Magaril M, et al., 2017, Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation, NATURE GENETICS, Vol: 49, Pages: 1522-+, ISSN: 1061-4036
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- Citations: 171
Burren OS, Garcia AR, Javierre B-M, et al., 2017, Chromosome contacts in activated T cells identify autoimmune disease candidate genes, GENOME BIOLOGY, Vol: 18, ISSN: 1474-760X
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- Citations: 47
Petersen R, Lambourne JJ, Javierre BM, et al., 2017, Platelet function is modified by common sequence variation in megakaryocyte super enhancers, NATURE COMMUNICATIONS, Vol: 8
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- Citations: 35
Taylor A, Dobnikar L, Spivakov M, et al., 2017, VASCULAR SMOOTH MUSCLE CELL HETEROGENEITY AND PLASTICITY, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A138-A138, ISSN: 1355-6037
Siersbaek R, Madsen JGS, Javierre BM, et al., 2017, Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation, MOLECULAR CELL, Vol: 66, Pages: 420-+, ISSN: 1097-2765
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- Citations: 133
Freire-Pritchett P, Schoenfeldern S, Varnai C, et al., 2017, Global reorganisation of <i>cis</i>-regulatory units upon lineage commitment of human embryonic stem cells, ELIFE, Vol: 6, ISSN: 2050-084X
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- Citations: 86
Stunnenberg HG, Hirst M, 2016, The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery, CELL, Vol: 167, Pages: 1145-1149, ISSN: 0092-8674
Javierre BM, Burren OS, Wilder SP, et al., 2016, Lineage-Specific Genome Architecture Links Enhancers and Non-coding Disease Variants to Target Gene Promoters, CELL, Vol: 167, Pages: 1369-+, ISSN: 0092-8674
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- Citations: 409
Spivakov M, Fraser P, 2016, Defining cell type with chromatin profiling, NATURE BIOTECHNOLOGY, Vol: 34, Pages: 1126-1128, ISSN: 1087-0156
Astle W, Elding H, Jiang T, et al., 2016, A High-resolution Genetic Atlas of Blood Cell Variation and Function in Humans, AABB Annual Meeting, Publisher: WILEY-BLACKWELL, Pages: 152A-152A, ISSN: 0041-1132
Schofield EC, Carver T, Achuthan P, et al., 2016, CHiCP: a web-based tool for the integrative and interactive visualization of promoter capture Hi-C datasets, BIOINFORMATICS, Vol: 32, Pages: 2511-2513, ISSN: 1367-4803
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- Citations: 54
Pancaldi V, Carrillo-de-Santa-Pau E, Javierre BM, et al., 2016, Integrating epigenomic data and 3D genomic structure with a new measure of chromatin assortativity, Genome Biology, Vol: 17, ISSN: 1474-7596
BackgroundNetwork analysis is a powerful way of modeling chromatin interactions. Assortativity is a network property used in social sciences to identify factors affecting how people establish social ties. We propose a new approach, using chromatin assortativity, to integrate the epigenomic landscape of a specific cell type with its chromatin interaction network and thus investigate which proteins or chromatin marks mediate genomic contacts.ResultsWe use high-resolution promoter capture Hi-C and Hi-Cap data as well as ChIA-PET data from mouse embryonic stem cells to investigate promoter-centered chromatin interaction networks and calculate the presence of specific epigenomic features in the chromatin fragments constituting the nodes of the network. We estimate the association of these features with the topology of four chromatin interaction networks and identify features localized in connected areas of the network. Polycomb group proteins and associated histone marks are the features with the highest chromatin assortativity in promoter-centered networks. We then ask which features distinguish contacts amongst promoters from contacts between promoters and other genomic elements. We observe higher chromatin assortativity of the actively elongating form of RNA polymerase 2 (RNAPII) compared with inactive forms only in interactions between promoters and other elements.ConclusionsContacts among promoters and between promoters and other elements have different characteristic epigenomic features. We identify a possible role for the elongating form of RNAPII in mediating interactions among promoters, enhancers, and transcribed gene bodies. Our approach facilitates the study of multiple genome-wide epigenomic profiles, considering network topology and allowing the comparison of chromatin interaction networks.
Cairns J, Freire-Pritchett P, Wingett SW, et al., 2016, CHiCAGO: robust detection of DNA looping interactions in Capture Hi-C data, Genome Biology, Vol: 17, Pages: 127-127, ISSN: 1474-7596
Capture Hi-C (CHi-C) is a method for profiling chromosomal interactions involving targeted regions of interest, such as gene promoters, globally and at high resolution. Signal detection in CHi-C data involves a number of statistical challenges that are not observed when using other Hi-C-like techniques. We present a background model and algorithms for normalisation and multiple testing that are specifically adapted to CHi-C experiments. We implement these procedures in CHiCAGO ( http://regulatorygenomicsgroup.org/chicago ), an open-source package for robust interaction detection in CHi-C. We validate CHiCAGO by showing that promoter-interacting regions detected with this method are enriched for regulatory features and disease-associated SNPs.
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