Professor David Tremethick
Although it has now been eighteen years since the human genome was completely sequenced, how this genomic information is selectively utilised to direct patterns of gene transcription and pre-mRNA splicing remains poorly understood. However, it has been well established that different epigenetic modifications, such as histone post-translational modifications (PTMs) and the substitution of core histones with their variant forms, play an important role in controlling all stages of the transcription process by modulating the accessibility of DNA. Collectively, this epigenetic-based information at a genome-wide level has been referred to as the epigenome, and there is also now overwhelming evidence that it is the epigenome that co-ordinates the gene expression pattern unique to each different cell type in the human body.
Our work has demonstrated that the exchange of the core histone H2A with its variant forms, in particular the essential histone variant H2A.Z, represents one of the most profound and crucial epigenetic processes that is required for early metazoan development, chromosome organisation and inheritance, as well as regulating promoter chromatin architecture to maintain or change cell fate. Mechanistically, we demonstrated that H2A.Z, and other types of H2A variants, performs these crucial functions by directly regulating the extent of chromatin compaction. Recently, we have also found that histone H2A variants are located at intron-exon boundaries to regulate pre-mRNA splicing, which is critical for male fertility and brain function. Moreover, we have found that the mis-incorporation of histone H2A variants into chromatin plays an important role in the progression of cancer.
To further understand the role of the epigenome, including the role of histone variants, in regulating genome function, we have established long-range genome mapping and computational 3D genome modelling approaches, which revealed how active and inactive genes are packaged and segregated into different 3-dimensional compartments within a chromosome during the differentiation of human stem cells.
However, despite these advances in knowledge, key questions remain unanswered: 1) how does the local ‘nucleosome beads-on-a string’ structure of chromatin fold into large spatially organised 3D structures and the role of histone variants in this process? 2) What is the mechanism of how histone variants regulate RNA processing, and its link with brain function and cancer? and 3) How does the epigenome co-ordinately regulate patterns of gene expression at a global level to control cell function?
- Supervisor, To determine the role of histone variants, and other important epigenetic regulators, in regulating gene transcription and splicing.
- Supervisor, To elucidate the role of the epigenome, including the histone variant H2A.Z, in regulating the 3-dimensional architecture of the genome by inhibiting the expression of epigenetic regulators cellular differentiation.
- Supervisor, To study the role of histone variants and other epigenetic regulators in controlling pre-mRNA splicing on brain function and spermatogenesis using mouse knockout models.
- Paulsen, J, Ali, T, Nekrasov, M et al 2019, 'Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation', Nature Genetics, vol. 51, no. 5, pp. 835-843.
- Anuar, N, Kurscheid, S, Field, M et al 2019, 'Gene editing of the multi-copy H2A.B gene and its importance for fertility 06 Biological Sciences 0604 Genetics Jin-Soo Kim', Genome Biology, vol. 20, no. 1, pp. -.
- Soboleva, T & Tremethick, D 2018, 'RChIP-Seq: Chromatin-Associated RNA Sequencing in Developmentally Staged Mouse Testes', in Guillermo A. Orsi and GeneviÃ¨ve Almouzni (ed.), Histone Variants: Methods and Protocols, Humana Press, New York, pp. 169-184.
- Ryan, D & Tremethick, D 2018, 'The interplay between H2A.Z and H3K9 methylation in regulating HP1α binding to linker histone-containing chromatin', Nucleic Acids Research, vol. 46, no. 18, pp. 9353-9366pp.
- Tasset, C, Yadav, A, Sureshkumar, S et al. 2018, 'POWERDRESS-mediated histone deacetylation is essential for thermomorphogenesis in Arabidopsis thaliana', PLoS Genetics, vol. 14, no. 3, pp. 1-21.
- Soboleva, T, Parker, B, Nekrasov, M et al 2017, 'A new link between transcriptional initiation and pre-mRNA splicing: The RNA binding histone variant H2A.B', PLoS Genetics, vol. 13, no. 2, pp. e1006633-e1006633.
- Moretti, C, Serrentino, M, Ialy-Radio, C et al 2017, 'SLY regulates genes involved in chromatin remodeling and interacts with TBL1XR1 during sperm differentiation', Cell Death and Differentiation, vol. 24, no. 6, pp. 1029-1044.
- Domaschenz, R, Kurscheid, S, Nekrasov, M et al 2017, 'The Histone Variant H2A.Z Is a Master Regulator of the Epithelial-Mesenchymal Transition', Cell Reports, vol. 21, no. 4, pp. 943-952.
- Ryan, D & Tremethick, D 2016, 'A dual affinity-tag strategy for the expression and purification of human linker histone H1.4 in Escherichia coli', Protein Expression and Purification, vol. 120, pp. 160-168.
- Soboleva, T, Nekrasov, M, Ryan, D et al 2014, 'Histone variants at the transcription start-site', Trends in Genetics, vol. 30, no. 5, pp. 199-209.
- Nekrasov, M, Soboleva, T, Jack, C et al 2013, 'Histone variant selectivity at the transcription start site H2A.Z or H2A.Lap1', Nucleus, vol. 4, no. 6, pp. 431-437.
- Talbert, P, Ahmad, K, Almouzni, G et al 2012, 'A unified phylogeny-based nomenclature for histone variants', Epigenetics and Chromatin, vol. 5, no. 1.
- Luger, K, Mekonnen, D & Tremethick, D 2012, 'New insights into nucleosome and chromatin structure: An ordered state or a disordered affair?', Nature Reviews: Molecular Cell Biology, vol. 13, no. 7, pp. 436-447.
- Valdes-Mora, F, Song, J, Statham, A et al 2012, 'Acetylation of H2A.Z is a key epigenetic modification associated with gene deregulation and epigenetic remodeling in cancer', Genome Research, vol. 22, no. 2, pp. 307-321.
- Nekrasov, M, Amrichova, J, Parker, B et al., 'Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics', Nature Structural and Molecular Biology. 2012, vol. 19, no. 11, pp. 1076-1083.
- Soboleva TA, Nekrasov M, Pahwa A, Williams R, Huttley GA, Tremethick DJ. 'A unique H2A histone variant occupies the transcriptional start site of active genes', Nature Structural and Molecular Biology. 2012 Jan; 19(1): 25-30.
- Koina, E, Chaumeil, J, Greaves, I et al 2009, 'Specific patterns of histone marks accompany X chromosome inactivation in a marsupial', Chromosome Research, vol. 17, pp. 115-126.
- Juelich, T, Sutcliffe, E, Denton, A et al. 2009, 'Interplay between chromatin remodeling and epigenetic changes during lineage-specific commitment to granzyme B expression', Journal of Immunology, vol. 183, pp. 7063-7072.
- Sutcliffe, EL, Parish, IA, He, YQ et al 2009, 'Dynamic histone variant exchange accompanies gene induction in T cells', Molecular and Cellular Biology, vol. 29, no. 7, pp. 1972-1986.
- Rangasamy, D, Tremethick, D & Greaves, I 2008, 'Gene knockdown by ecdysone-based inducible RNAi in stable mammalian cell lines', Nature Protocols, vol. 3, no. 1, pp. 79-88.
- Wagstaff, K, Fan, J, De Jesus, M et al 2008, 'Efficient gene delivery using reconstituted chromatin enhanced for nuclear targeting', The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol. 22, no. 7, pp. 2232-42.
- Tremethick, D 2007, 'Higher-order structures of chromatin: the elusive 30 nm fiber', Cell, vol. 128, no. 4, pp. 651-654.
- Wagstaff, K, Glover, D, Tremethick, D et al 2007, 'Histone-mediated transduction as an efficient means for gene delivery', Molecular therapy : the journal of the American Society of Gene Therapy, vol. 15, no. 4, pp. 721-31.
- Zhou, J, Fan, J, Rangasamy, D et al 2007, 'The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression', Nature Structural and Molecular Biology, vol. 14, no. 11, pp. 1070-6.
- Greaves, I, Rangasamy, D, Ridgway, P et al 2007, 'H2A.Z contributes to the unique 3D structure of the centromere', PNAS - Proceedings of the National Academy of Sciences of the United States of America, vol. 104, pp. 525-30.
- Fan, J, Zhou, J & Tremethick, D 2007, 'Quantitative analysis of HP1alpha binding to nucleosomal arrays', Methods, vol. 41, no. 1, pp. 286-90.
- Tremethick, D 2006, 'Chromatin: the dynamic link between structure and function', Chromosome Research, vol. 14, no. 1, pp. 1-4.
- Yang, M, Rangasamy, D, Matthaei, K et al. 2006, 'Inhibition of Arginase I Activity by RNA Interference Attenuates IL-13-Induced Airways Hyperresponsiveness', Journal of Immunology, vol. 177, no. 8, pp. 5595-603.
- Bulynko, Y, Hsing, L, Mason, R et al 2006, 'Cathepsin L stabilizes the histone modification landscape on the y chromosome and pericentromeric heterochromatin', Molecular and Cellular Biology, vol. 26, no. 11, pp. 4172-4184.
- Greaves, I, Rangasamy, D, Devoy, M et al 2006, 'The X and Y chromosomes assemble into H2A.Z, containing facultative heterochromatin, following meiosis', Molecular and Cellular Biology, vol. 26, no. 14, pp. 5394-405.
- Bruce, K, Myers, F, Mantouvalou, E et al 2005, 'The replacement histone H2A.Z in a hyperacetylated form is a feature of active genes in the chicken', Nucleic Acids Research, vol. 33, no. 17, pp. 5633-5639.
- Chakravarthy, S, Bao, Y, Roberts, V et al 2005, 'Structural characterization of histone H2A variants', Cold Spring Harbour Symposia on Quantitative Biology, vol. 69, pp. 227-234.
- Henderson, A, Holloway, A, Reeves, R et al. 2004, 'Recruitment of SWI/SNF to the Human Immunodeficiency Virus Type 1 Promoter', Molecular and Cellular Biology, vol. 24, no. 1, pp. 389-397.
- Ridgway, P, Brown, K, Rangasamy, D et al 2004, 'Unique Residues on the H2A.Z Containing Nucleosome Surface Are Important for Xenopus laevis Development', Journal of Biological Chemistry, vol. 279, no. 42, pp. 43815-43820.
- Rangasamy, D, Greaves, I & Tremethick, D 2004, 'RNA interference demonstrates a novel role for H2A.Z in chromosome segregation', Nature Structural and Molecular Biology, vol. 11, no. 7, pp. 650-655.
- Park, Y, Dyer, P, Tremethick, D et al 2004, 'A New Fluorescence Resonance Energy Transfer Approach Demonstrates That the Histone Variant H2AZ Stabilizes the Histone octamer within the Nucleosome', Journal of Biological Chemistry, vol. 279, no. 23, pp. 24274-24282.
- Fan, J, Rangasamy, D, Luger, K et al 2004, 'H2A.Z Alters the Nucleosome Surface to Promote HP1ï¿½-Mediated Chromatin Fiber Folding', Molecular Cell, vol. 16, pp. 655-661.
- Bao, Y, Konesky, K, Park, Y et al 2004, 'Nucleosomes containing the histone variant H2A.Bbd organize only 118 base pairs of DNA', The EMBO Journal, vol. 23, no. 16, pp. 3314-3324.
- Ridgway, P, Rangasamy, D, Berven, L et al 2004, 'Analysis of Histone Variant H2A.Z localisation and expression during early development', Methods in Enzymology, vol. 375, pp. 239-252.
- Rangasamy, D, Berven, L, Ridgway, P et al 2003, 'Pericentric heterochromatin becomes enriched with H2A.Z during early mammalian development', The EMBO Journal, vol. 22, pp. 1599-1607.
- Dogra, S, Tremethick, D & May, F 2003, 'Evidence That the Coactivator CBP/p300 Is Important for Phenobarbital-Induced but Not Basal Expression of the CYP2H1 Gene', Molecular Pharmacology, vol. 63, no. 1, pp. 73-80.
- Fan, J, Gordon, F, Luger, K et al 2002, 'The essential histone variant H2A.Z regulates the equilibrium between different chromatin conformational states', Nature Structural Biology, vol. 9, no. 3, pp. 172-176.
- Attema, J, Reeves, R, Murray, V et al. 2002, 'The human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation.', Journal of Immunology, vol. 169, pp. 2466-2476.
- Faast, R, Thonglairoam, V, Schulz, T et al 2001, 'Histone variant H2A.Z is required for early mammalian development', Current Biology, vol. 11, pp. 1183-187.
- Henderson, A, Bunce, M, Siddon, N et al. 2000, 'High-Mobility-Group Protein I Can Modulate Binding of Transcription Factors to the U5 Region of the Human Immunodificiency Virus Type 1 Proviral Promoter', Journal of Virology, vol. 74, pp. 10523-10534.
- Johnson-Saliba, M, Siddon, N, Clarkson, M et al. 2000, 'Distinct importin recognition properties of histones and chromatin assembly factors.', FEBS Letters, vol. 467, pp. 169-174.
- Guschin, D, Geiman, T, Kikyo, N et al 2000, 'A Multiple ISWI ATPase complexes from Xenopus laevis', Journal of Biological Chemistry, vol. 2750, pp. 35248-35255.
- Tremethick, D 1999, 'Chromatin assembly in xenopus extracts', Methods in Enzymology, vol. 304, pp. 50-63.