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Author Mikhail Spivakov

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TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation.

Jessica Sook Yuin Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph A Wayman, Natasha N Gaudreault, David A Meekins, Sabarish V Indran, Igor Morozov, Jessie D Trujillo, Yesai S Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya Malysheva, Michiel J Thiecke, Siu-Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak-Yiu Lee, Wen-Chun Liu, Sonia Jangra, Alba Escalera, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David A Kaufman, Andre L Moreira, Mariano Carossino, Udeni B R Balasuriya, Minji Byun, Randy A Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit K Chanda, Emily R Miraldi, Anand D Jeyasekharan, Benjamin R TenOever, Mikhail Spivakov, Matthew T Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen A Richt, Ivan Marazzi,

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo ... Read more >>

Cell (Cell)
[2021, 184(10):2618-2632.e17]

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]

Cited: 0 times

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Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models

Jessica Sook Yuin Ho, Bobo Wing-Yee Mok, Laura Campisi, Tristan Jordan, Soner Yildiz, Sreeja Parameswaran, Joseph Wayman, Natasha Gaudreault, David Meekins, Sabarish Indran, Igor Morozov, Jessie Trujillo, Yesai Fstkchyan, Raveen Rathnasinghe, Zeyu Zhu, Simin Zheng, Nan Zhao, Kris White, Helen Ray-Jones, Valeriya Malysheva, Michiel Thiecke, Siu-Ying Lau, Honglian Liu, Anna Junxia Zhang, Andrew Chak-Yiu Lee, Wen-Chun Liu, Teresa Aydillo, Betsaida Salom Melo, Ernesto Guccione, Robert Sebra, Elaine Shum, Jan Bakker, David Kaufman, Andre Moreira, Mariano Carossino, Udeni Balasuriya, Minji Byun, Emily Miraldi, Randy Albrecht, Michael Schotsaert, Adolfo Garcia-Sastre, Sumit Chanda, Anand Jeyasekharan, Benjamin TenOever, Mikhail Spivakov, Matthew Weirauch, Sven Heinz, Honglin Chen, Christopher Benner, Juergen Richt, Ivan Marazzi,

<h4>SUMMARY</h4> The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro ... Read more >>

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Primed smooth muscle cells acting as first responder cells in disease

Matt Worssam, Jordi Lambert, Sebnem Oc, Annabel Taylor, Lina Dobnikar, Joel Chappell, Jennifer Harman, Nichola Figg, Alison Finigan, Kirsty Foote, Anna Uryga, Martin Bennett, Mikhail Spivakov, Helle Jørgensen,

<h4>ABSTRACT</h4> <h4>Rationale</h4> Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation ... Read more >>

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Silencers in the spotlight.

Monica Della Rosa, Mikhail Spivakov,

Nat Genet (Nature genetics)
[2020, 52(3):244-245]

Cited: 2 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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Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters.

Joanna Mitchelmore, Nastasiya F Grinberg, Chris Wallace, Mikhail Spivakov,

Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in ... Read more >>

Nucleic Acids Res (Nucleic acids research)
[2020, 48(6):2866-2879]

Cited: 3 times

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Chicdiff: a computational pipeline for detecting differential chromosomal interactions in Capture Hi-C data.

Jonathan Cairns, William R Orchard, Valeriya Malysheva, Mikhail Spivakov,

<h4>Summary</h4>Capture Hi-C is a powerful approach for detecting chromosomal interactions involving, at least on one end, DNA regions of interest, such as gene promoters. We present Chicdiff, an R package for robust detection of differential interactions in Capture Hi-C data. Chicdiff enhances a state-of-the-art differential testing approach for count data ... Read more >>

Bioinformatics (Bioinformatics (Oxford, England))
[2019, 35(22):4764-4766]

Cited: 5 times

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Functional effects of variation in transcription factor binding highlight long-range gene regulation by epromoters

Joanna Mitchelmore, Nastasiya Grinberg, Chris Wallace, Mikhail Spivakov,

Identifying DNA cis-regulatory modules (CRMs) that control the expression of specific genes is crucial for deciphering the logic of transcriptional control. Natural genetic variation can point to the possible gene regulatory function of specific sequences through their allelic associations with gene expression. However, comprehensive identification of causal regulatory sequences in ... 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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Chicdiff: a computational pipeline for detecting differential chromosomal interactions in Capture Hi-C data

Jonathan Cairns, William Orchard, Valeriya Malysheva, Mikhail Spivakov,

<h4>Summary</h4> Capture Hi-C is a powerful approach for detecting chromosomal interactions involving, at least on one end, DNA regions of interest, such as gene promoters. We present Chicdiff, an R package for robust detection of differential interactions in Capture Hi-C data. ChiScdiff enhances a state-of-the-art differential testing approach for count ... Read more >>

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Publisher Correction: Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

Lina Dobnikar, Annabel L Taylor, Joel Chappell, Phoebe Oldach, Jennifer L Harman, Erin Oerton, Elaine Dzierzak, Martin R Bennett, Mikhail Spivakov, Helle F Jørgensen,

The original version of this Article contained errors in the author affiliations.Martin R. Bennett was incorrectly associated with Nuclear Dynamics Programme, Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, Phoebe Oldach was incorrectly associated ... Read more >>

Nat Commun (Nature communications)
[2018, 9(1):5401]

Cited: 1 time

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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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Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels.

Lina Dobnikar, Annabel L Taylor, Joel Chappell, Phoebe Oldach, Jennifer L Harman, Erin Oerton, Elaine Dzierzak, Martin R Bennett, Mikhail Spivakov, Helle F Jørgensen,

Vascular smooth muscle cells (VSMCs) show pronounced heterogeneity across and within vascular beds, with direct implications for their function in injury response and atherosclerosis. Here we combine single-cell transcriptomics with lineage tracing to examine VSMC heterogeneity in healthy mouse vessels. The transcriptional profiles of single VSMCs consistently reflect their region-specific ... Read more >>

Nat Commun (Nature communications)
[2018, 9(1):4567]

Cited: 46 times

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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,

Long-range chromosomal interactions bring distal regulatory elements and promoters together to regulate gene expression in biological processes. By performing promoter capture Hi-C (PCHi-C) on human embryonic stem cell-derived cardiomyocytes (hESC-CMs), we show that such promoter interactions are a key mechanism by which enhancers contact their target genes after hESC-CM differentiation ... Read more >>

Nat Commun (Nature communications)
[2018, 9(1):2526]

Cited: 9 times

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Genome organization and chromatin analysis identify transcriptional downregulation of insulin-like growth factor signaling as a hallmark of aging in developing B cells.

Hashem Koohy, Daniel J Bolland, Louise S Matheson, Stefan Schoenfelder, Claudia Stellato, Andrew Dimond, Csilla Várnai, Peter Chovanec, Tamara Chessa, Jeremy Denizot, Raquel Manzano Garcia, Steven W Wingett, Paula Freire-Pritchett, Takashi Nagano, Phillip Hawkins, Len Stephens, Sarah Elderkin, Mikhail Spivakov, Peter Fraser, Anne E Corcoran, Patrick D Varga-Weisz,

<h4>Background</h4>Aging 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 ... Read more >>

Genome Biol (Genome biology)
[2018, 19(1):126]

Cited: 6 times

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Gene regulatory network reconstruction incorporating 3D chromosomal architecture reveals key transcription factors and DNA elements driving neural lineage commitment

Valeriya Malysheva, Marco Antonio Mendoza-Parra, Matthias Blum, Mikhail Spivakov, Hinrich Gronemeyer,

Lineage commitment is a fundamental process that enables the morphogenesis of multicellular organisms from a single pluripotent cell. While many genes involved in the commitment to specific lineages are known, the logic of their joint action is incompletely understood, and predicting the effects of genetic perturbations on lineage commitment is ... Read more >>

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DNA methylation oscillation defines classes of enhancers

Emanuele Libertini, Rifat Hamoudi, Simon Heath, Lee Lancashire, Arcadio Rubio Garcia, Luigi Grassi, Kate Downes, Willem Ouwehand, Biola-Maria Javierre, Jonathan Cairns, Steven Wingett, Dirk Paul, Marta Gut, Ivo Gut, Joost Martens, Alexandr Ivliev, Hendrik Stunnenberg, Mattia Frontini, Mikhail Spivakov, Peter Fraser, Antony Cutler, Chris Wallace, Stephan Beck,

Understanding the regulatory landscape of human cells requires the integration of genomic and epigenomic maps, capturing combinatorial levels of cell type-specific and invariant activity states. Here, we segmented whole-genome bisulfite sequencing-derived methylomes into consecutive blocks of co-methylation (COMETs) to obtain spatial variation patterns of DNA methylation (DNAm oscillations) integrated with ... Read more >>

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Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation.

Adam J Rubin, Brook C Barajas, Mayra Furlan-Magaril, Vanessa Lopez-Pajares, Maxwell R Mumbach, Imani Howard, Daniel S Kim, Lisa D Boxer, Jonathan Cairns, Mikhail Spivakov, Steven W Wingett, Minyi Shi, Zhixin Zhao, William J Greenleaf, Anshul Kundaje, Michael Snyder, Howard Y Chang, Peter Fraser, Paul A Khavari,

Chromosome conformation is an important feature of metazoan gene regulation; however, enhancer-promoter contact remodeling during cellular differentiation remains poorly understood. To address this, genome-wide promoter capture Hi-C (CHi-C) was performed during epidermal differentiation. Two classes of enhancer-promoter contacts associated with differentiation-induced genes were identified. The first class ('gained') increased in ... Read more >>

Nat Genet (Nature genetics)
[2017, 49(10):1522-1528]

Cited: 79 times

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Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells.

Paula Freire-Pritchett, Stefan Schoenfelder, Csilla Várnai, Steven W Wingett, Jonathan Cairns, Amanda J Collier, Raquel García-Vílchez, Mayra Furlan-Magaril, Cameron S Osborne, Peter Fraser, Peter J Rugg-Gunn, Mikhail Spivakov,

Long-range <i>cis-</i>regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of <i>cis-</i>regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a ... Read more >>

Elife (eLife)
[2017, 6:]

Cited: 35 times

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Platelet function is modified by common sequence variation in megakaryocyte super enhancers.

Romina Petersen, John J Lambourne, Biola M Javierre, Luigi Grassi, Roman Kreuzhuber, Dace Ruklisa, Isabel M Rosa, Ana R Tomé, Heather Elding, Johanna P van Geffen, Tao Jiang, Samantha Farrow, Jonathan Cairns, Abeer M Al-Subaie, Sofie Ashford, Antony Attwood, Joana Batista, Heleen Bouman, Frances Burden, Fizzah A Choudry, Laura Clarke, Paul Flicek, Stephen F Garner, Matthias Haimel, Carly Kempster, Vasileios Ladopoulos, An-Sofie Lenaerts, Paulina M Materek, Harriet McKinney, Stuart Meacham, Daniel Mead, Magdolna Nagy, Christopher J Penkett, Augusto Rendon, Denis Seyres, Benjamin Sun, Salih Tuna, Marie-Elise van der Weide, Steven W Wingett, Joost H Martens, Oliver Stegle, Sylvia Richardson, Ludovic Vallier, David J Roberts, Kathleen Freson, Lorenz Wernisch, Hendrik G Stunnenberg, John Danesh, Peter Fraser, Nicole Soranzo, Adam S Butterworth, Johan W Heemskerk, Ernest Turro, Mikhail Spivakov, Willem H Ouwehand, William J Astle, Kate Downes, Myrto Kostadima, Mattia Frontini,

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data ... Read more >>

Nat Commun (Nature communications)
[2017, 8:16058]

Cited: 21 times

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Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.

Rasmus Siersbæk, Jesper Grud Skat Madsen, Biola Maria Javierre, Ronni Nielsen, Emilie Kristine Bagge, Jonathan Cairns, Steven William Wingett, Sofie Traynor, Mikhail Spivakov, Peter Fraser, Susanne Mandrup,

Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr ... Read more >>

Mol Cell (Molecular cell)
[2017, 66(3):420-435.e5]

Cited: 59 times

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Defining cell type with chromatin profiling.

Mikhail Spivakov, Peter Fraser,

Nat Biotechnol (Nature biotechnology)
[2016, 34(11):1126-1128]

Cited: 2 times

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Chromosome contacts in activated T cells identify autoimmune disease candidate genes

Oliver Burren, Arcadio Rubio García, Biola-Maria Javierre, Daniel Rainbow, Jonathan Cairns, Nicholas Cooper, John Lambourne, Ellen Schofield, Xaquin Castro Dopico, Ricardo Ferreira, Richard Coulson, Frances Burden, Sophia Rowlston, Kate Downes, Steven Wingett, Mattia Frontini, Willem Ouwehand, Peter Fraser, Mikhail Spivakov, John Todd, Linda Wicker, Antony Cutler, Chris Wallace,

<h4>Background</h4> Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4 + T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. <h4>Results</h4> Within four hours, activation of CD4 + T cells invokes changes in histone modifications ... Read more >>

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Integrating epigenomic data and 3D genomic structure with a new measure of chromatin assortativity.

Vera Pancaldi, Enrique Carrillo-de-Santa-Pau, Biola Maria Javierre, David Juan, Peter Fraser, Mikhail Spivakov, Alfonso Valencia, Daniel Rico,

<h4>Background</h4>Network 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 ... Read more >>

Genome Biol (Genome biology)
[2016, 17(1):152]

Cited: 15 times

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