8 results on '"Maxim Nekrasov"'
Search Results
2. Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans
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Henry J. Sutton, Racheal Aye, Azza H. Idris, Rachel Vistein, Eunice Nduati, Oscar Kai, Jedida Mwacharo, Xi Li, Xin Gao, T. Daniel Andrews, Marios Koutsakos, Thi H.O. Nguyen, Maxim Nekrasov, Peter Milburn, Auda Eltahla, Andrea A. Berry, Natasha KC, Sumana Chakravarty, B. Kim Lee Sim, Adam K. Wheatley, Stephen J. Kent, Stephen L. Hoffman, Kirsten E. Lyke, Philip Bejon, Fabio Luciani, Katherine Kedzierska, Robert A. Seder, Francis M. Ndungu, and Ian A. Cockburn
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B cell memory ,atypical B cells ,alternative B cell lineage ,malaria ,sporozoite ,vaccination ,Biology (General) ,QH301-705.5 - Abstract
Summary: The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses.
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- 2021
- Full Text
- View/download PDF
3. The Histone Variant H2A.Z Is a Master Regulator of the Epithelial-Mesenchymal Transition
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Renae Domaschenz, Sebastian Kurscheid, Maxim Nekrasov, Shuyi Han, and David J. Tremethick
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Biology (General) ,QH301-705.5 - Abstract
Summary: Epithelial-mesenchymal transition (EMT) is a profound example of cell plasticity that is crucial for embryonic development and cancer. Although it has long been suspected that chromatin-based mechanisms play a role in this process, no master regulator that can specifically regulate EMT has been identified to date. Here, we show that H2A.Z can coordinate EMT by serving as either an activator or repressor of epithelial or mesenchymal gene expression, respectively. Following induction of EMT by TGF-β, we observed an unexpected loss of H2A.Z across both downregulated epithelial and upregulated mesenchymal promoters. Strikingly, the repression of epithelial gene expression was associated with reduction of H2A.Z upstream of the transcription start site (TSS), while the activation of mesenchymal gene expression was dependent on removal of H2A.Z downstream of the TSS. Therefore, the ability of H2A.Z to regulate EMT is dependent on its position, either upstream or downstream of the TSS. : EMT is one of the most intensely studied differentiation-dedifferentiation processes. Domaschenz et al. now demonstrate that H2A.Z has the unique ability to simultaneously serve as either an activator or a repressor of epithelial or mesenchymal gene expression, respectively. Keywords: EMT, H2A.Z, nucleosomes, TGF-β, gene regulation, promoter organization, cell plasticity, differentiation, chromatin
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- 2017
- Full Text
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4. POWERDRESS-mediated histone deacetylation is essential for thermomorphogenesis in Arabidopsis thaliana.
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Celine Tasset, Avilash Singh Yadav, Sridevi Sureshkumar, Rupali Singh, Lennard van der Woude, Maxim Nekrasov, David Tremethick, Martijn van Zanten, and Sureshkumar Balasubramanian
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Genetics ,QH426-470 - Abstract
Ambient temperature affects plant growth and even minor changes can substantially impact crop yields. The underlying mechanisms of temperature perception and response are just beginning to emerge. Chromatin remodeling, via the eviction of the histone variant H2A.Z containing nucleosomes, is a critical component of thermal response in plants. However, the role of histone modifications remains unknown. Here, through a forward genetic screen, we identify POWERDRESS (PWR), a SANT-domain containing protein known to interact with HISTONE DEACETYLASE 9 (HDA9), as a novel factor required for thermomorphogenesis in Arabidopsis thaliana. We show that mutations in PWR impede thermomorphogenesis, exemplified by attenuated warm temperature-induced hypocotyl/petiole elongation and early flowering. We show that inhibitors of histone deacetylases diminish temperature-induced hypocotyl elongation, which demonstrates a requirement for histone deacetylation in thermomorphogenesis. We also show that elevated temperature is associated with deacetylation of H3K9 at the +1 nucleosomes of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and YUCCA8 (YUC8), and that PWR is required for this response. There is global misregulation of genes in pwr mutants at elevated temperatures. Meta-analysis revealed that genes that are misregulated in pwr mutants display a significant overlap with genes that are H2A.Z-enriched in their gene bodies, and with genes that are differentially expressed in mutants of the components of the SWR1 complex that deposits H2A.Z. Our findings thus uncover a role for PWR in facilitating thermomorphogenesis and suggest a potential link between histone deacetylation and H2A.Z nucleosome dynamics in plants.
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- 2018
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5. A new link between transcriptional initiation and pre-mRNA splicing: The RNA binding histone variant H2A.B.
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Tatiana A Soboleva, Brian J Parker, Maxim Nekrasov, Gene Hart-Smith, Ying Jin Tay, Wei-Quan Tng, Marc Wilkins, Daniel Ryan, and David J Tremethick
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Genetics ,QH426-470 - Abstract
The replacement of histone H2A with its variant forms is critical for regulating all aspects of genome organisation and function. The histone variant H2A.B appeared late in evolution and is most highly expressed in the testis followed by the brain in mammals. This raises the question of what new function(s) H2A.B might impart to chromatin in these important tissues. We have immunoprecipitated the mouse orthologue of H2A.B, H2A.B.3 (H2A.Lap1), from testis chromatin and found this variant to be associated with RNA processing factors and RNA Polymerase (Pol) II. Most interestingly, many of these interactions with H2A.B.3 (Sf3b155, Spt6, DDX39A and RNA Pol II) were inhibited by the presence of endogenous RNA. This histone variant can bind to RNA directly in vitro and in vivo, and associates with mRNA at intron-exon boundaries. This suggests that the ability of H2A.B to bind to RNA negatively regulates its capacity to bind to these factors (Sf3b155, Spt6, DDX39A and RNA Pol II). Unexpectedly, H2A.B.3 forms highly decompacted nuclear subdomains of active chromatin that co-localizes with splicing speckles in male germ cells. H2A.B.3 ChIP-Seq experiments revealed a unique chromatin organization at active genes being not only enriched at the transcription start site (TSS), but also at the beginning of the gene body (but being excluded from the +1 nucleosome) compared to the end of the gene. We also uncover a general histone variant replacement process whereby H2A.B.3 replaces H2A.Z at intron-exon boundaries in the testis and the brain, which positively correlates with expression and exon inclusion. Taken together, we propose that a special mechanism of splicing may occur in the testis and brain whereby H2A.B.3 recruits RNA processing factors from splicing speckles to active genes following its replacement of H2A.Z.
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- 2017
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6. Multiple roles of H2A.Z in regulating promoter chromatin architecture in human cells
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David J. Tremethick, Renae Domaschenz, Maxim Nekrasov, Sebastian Kurscheid, Daniel L. Vera, Lauren Cole, and Jonathan H. Dennis
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Epigenomics ,0301 basic medicine ,Nucleosome organization ,animal structures ,Science ,Gene Expression ,General Physics and Astronomy ,RNA polymerase II ,Article ,General Biochemistry, Genetics and Molecular Biology ,Histones ,03 medical and health sciences ,Chromatin analysis ,0302 clinical medicine ,Cell Line, Tumor ,Gene expression ,Humans ,Micrococcal Nuclease ,Nucleosome ,Promoter Regions, Genetic ,Histone variants ,Binding Sites ,Multidisciplinary ,biology ,Chemistry ,Promoter ,General Chemistry ,Chromatin ,Nucleosomes ,Cell biology ,DNA binding site ,030104 developmental biology ,Histone ,embryonic structures ,biology.protein ,RNA Polymerase II ,Transcription ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Chromatin accessibility of a promoter is fundamental in regulating transcriptional activity. The histone variant H2A.Z has been shown to contribute to this regulation, but its role has remained poorly understood. Here, we prepare high-depth maps of the position and accessibility of H2A.Z-containing nucleosomes for all human Pol II promoters in epithelial, mesenchymal and isogenic cancer cell lines. We find that, in contrast to the prevailing model, many different types of active and inactive promoter structures are observed that differ in their nucleosome organization and sensitivity to MNase digestion. Key aspects of an active chromatin structure include positioned H2A.Z MNase resistant nucleosomes upstream or downstream of the TSS, and a MNase sensitive nucleosome at the TSS. Furthermore, the loss of H2A.Z leads to a dramatic increase in the accessibility of transcription factor binding sites. Collectively, these results suggest that H2A.Z has multiple and distinct roles in regulating gene expression dependent upon its location in a promoter., Histone variant H2A.Z has been suggested to contribute to the regulation of promoter accessibility. Here, the authors present high-depth maps of the position and accessibility of H2A.Z-containing nucleosomes for human Pol II promoters and provide evidence that H2A.Z has multiple and distinct roles in regulating gene expression dependent upon its location in a promoter.
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- 2021
7. Histone variant selectivity at the transcription start site: H2A.Z or H2A.Lap1
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Cameron Jack, Maxim Nekrasov, David J. Tremethick, and Tatiana A. Soboleva
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Male ,RNA polymerase II ,H2A.Bbd ,Crystallography, X-Ray ,Protein Structure, Secondary ,Histones ,Mice ,Transcription (biology) ,Y Chromosome ,Histone methylation ,Promoter Regions, Genetic ,Oligonucleotide Array Sequence Analysis ,Regulation of gene expression ,Genetics ,Mice, Inbred BALB C ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cell Cycle ,H2A.Z ,Spermatids ,Chromatin ,Trophoblasts ,Nucleosomes ,ChIP-seq ,Meiosis ,Histone ,microarray gene expression analysis ,embryonic structures ,Transcription Initiation Site ,nucleosome positioning ,Protein Binding ,animal structures ,H2A.Lap1 ,X Chromosome ,Blotting, Western ,Molecular Sequence Data ,Models, Biological ,stem cells ,Histone H2A ,Nucleosome ,Animals ,Amino Acid Sequence ,histone variants ,Spermatogenesis ,Gene ,active chromatin ,the transcriptional start site ,Sequence Homology, Amino Acid ,Extra View ,Gene Expression Profiling ,Genetic Variation ,Cell Biology ,Gene Expression Regulation ,biology.protein - Abstract
Considerable attention has been given to the understanding of how nucleosomes are altered or removed from the transcription start site of RNA polymerase II genes to enable transcription to proceed. This has led to the view that for transcriptional activation to occur, the transcription start site (TSS) must become depleted of nucleosomes. However, we have shown that this is not the case with different unstable histone H2A variant-containing nucleosomes occupying the TSS under different physiological settings. For example, during mouse spermatogenesis we found that the mouse homolog of human H2A.Bbd, H2A.Lap1, is targeted to the TSS of active genes expressed during specific stages of spermatogenesis. On the other hand, we observed in trophoblast stem cells, a H2A.Z-containing nucleosome occupying the TSS of genes active in the G 1 phase of the cell cycle. Notably, this H2A.Z-containing nucleosome was different compared with other promoter specific H2A.Z nucleosomes by being heterotypic rather than being homotypic. In other words, it did not contain the expected two copies of H2A.Z per nucleosome but only one (i.e., H2A.Z/H2A rather than H2A.Z/H2A.Z). Given these observations, we wondered whether the histone variant composition of a nucleosome at an active TSS could in fact vary in the same cell type. To investigate this possibility, we performed H2A.Z ChIP-H2A reChIP assays in the mouse testis and compared this data with our testis H2A.Lap1 ChIP-seq data. Indeed, we find that different promoters involved in the expression of genes involved in distinct biological processes can contain either H2A.Z/H2A or H2A.Lap1. This argues that specific mechanisms exist, which can determine whether H2A.Z or H2A.Lap1 is targeted to the TSS of an active gene.
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- 2013
8. Nucleosome binding and histone methyltransferase activity of Drosophila PRC2
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Brigitte Wild, Maxim Nekrasov, and Jürg Müller
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Histone methyltransferase activity ,Chromosomal Proteins, Non-Histone ,Xenopus ,Scientific Report ,Electrophoretic Mobility Shift Assay ,macromolecular substances ,Biochemistry ,Methylation ,Histone H4 ,Histone H3 ,Histone methylation ,Genetics ,Nucleosome ,Animals ,Drosophila Proteins ,Gene Silencing ,Protein Methyltransferases ,Molecular Biology ,Polycomb Repressive Complex 1 ,Nucleosome binding ,biology ,Polycomb Repressive Complex 2 ,Nuclear Proteins ,Histone-Lysine N-Methyltransferase ,Molecular biology ,Chromatin ,Cell biology ,Nucleosomes ,Repressor Proteins ,Protein Subunits ,Histone ,Histone methyltransferase ,biology.protein ,Histone Methyltransferases ,Drosophila ,Retinoblastoma-Binding Protein 4 ,Baculoviridae ,Molecular Chaperones ,Plasmids - Abstract
The Drosophila Polycomb group protein E(z) is a histone methyltransferase (HMTase) that is essential for maintaining HOX gene silencing during development. E(z) exists in a multiprotein complex called Polycomb repressive complex 2 (PRC2) that also contains Su(z)12, Esc and Nurf55. Reconstituted recombinant PRC2 methylates nucleosomes in vitro, but recombinant E(z) on its own shows only poor HMTase activity on nucleosomes. Here, we investigate the function of the PRC2 subunits. We show that PRC2 binds to nucleosomes in vitro but that individual PRC2 subunits alone do not bind to nucleosomes. By analysing PRC2 subcomplexes, we show that Su(z)12–Nurf55 is the minimal nucleosome-binding module of PRC2 and that Esc contributes to high-affinity binding of PRC2 nucleosomes. We find that nucleosome binding of PRC2 is not sufficient for histone methylation and that only complexes that contain Esc protein show robust HMTase activity. These observations suggest that different subunits provide mechanistically distinct functions within the PRC2 HMTase: the nucleosome-binding subunits Su(z)12 and Nurf55 anchor the E(z) enzyme on chromatin substrates, whereas Esc is needed to boost enzymatic activity.
- Published
- 2005
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