Wellcome Principal Research Fellow
Robin Allshire is a Wellcome Principal Research Fellow and Professor of Chromosome Biology at the University of Edinburgh. After graduating from Trinity College Dublin, Ireland in 1981 with a BA in Genetics, he obtained a Royal Commission for the Exhibition of 1851 scholarship and studied for a PhD at the MRC Mammalian Genome Unit, Edinburgh (MRC HGU) with Dr. Chris Bostock and Ed Southern. Following post-doctoral research at the MRC HGU with Prof. N.D. Hastie, he began his independent research career in 1989 at Cold Spring Harbor Laboratories, New York. He returned to a tenured position at MRC HGU from 1990 to 2002 during which he took a three month research sabbatical with Prof. Mitsuhiro Yanagida at Kyoto University. In 2002, he moved to the Wellcome Centre for Cell Biology where he runs a dynamic research group as a Wellcome Principal Research Fellow (2002-2022). He was elected a member of the European Molecular Biology Organisation (EMBO) in 1998, a fellow of the Royal Society of Edinburgh (FRSE) in 2005 and a fellow of the Royal Society (FRS), London in 2011. He was awarded the Genetics Society (UK) Medal in 2013.
Epigenetic inheritance: establishment and transmission of specialised chromatin domains
Chromosomal DNA is wrapped around nucleosomes containing core histones (H3/H4/H2A/H2B). However, at centromeres a specific histone H3 variant, CENP-A, replaces histone H3 to form specialized CENP-A nucleosomes. CENP-A chromatin is critical for assembly of the chromosome segregation machinery – kinetochores – at these specific chromosomal locations and is flanked by histone H3 lysine 9 methylated heterochromatin.
Our goal is to decipher conserved mechanisms that establish, maintain and regulate the assembly of heterochromatin and CENP-A chromatin domains. Heterochromatin is required for the establishment of CENP-A chromatin on centromere DNA. One objective is to provide further insight into mechanisms that promote heterochromatin formation on pericentromeric repeats. Heterochromatin might also silence genes throughout the genome; we therefore also investigate how heterochromatin formation is regulated and whether such mechanisms influence phenotype. We endeavour to determine how heterochromatin, spatial nuclear organisation and non-coding RNAPII transcription combine to mediate CENP-A incorporation at centromeres.
Our main questions are:
1. How do DNA, RNA and chromatin signatures instigate the assembly of specialized chromatin domains?
2. How does chromatin architecture and subnuclear compartmentalization affect specialized chromatin domains?
3. How does heterochromatin influence gene expression?
A combination of next-generation sequencing technologies allowed the de novo assembly of the genomes of two fission yeast species that are evolutionarily distinct from Schizosaccharomyces pombe. Our assemblies are contiguous across all three centromeres, and other heterochromatin regions, of both species and permits comparison of centromere organization between these divergent species (Figure A). Centromeres from all three species retain an overall structural resemblance, however, no sequence similarity is detected between repetitive elements and central regions of even the closest two species.
Interspecies functional tests reveal that non-homologous S. octosporus and S. cryophilus centromere DNA is recognized and promotes functional centromere assembly in S. pombe. We surmise that conserved processes recognize features associated with non-conserved centromere DNA allowing preservation of centromere identity and location over evolutionary time. Conserved processes, such as transcription, may promote recognition of these centromeric DNAs and the replacement of histone H3 chromatin with CENP-A chromatin. Consistent with this concept, ectopic centromeric DNA, that has not assembled CENP-A or kinetochores, exhibits both the same H3 dynamics as existing centromeres during the cell cycle (Figure B) and a high rate of H3 turnover, similar to that seen on active genes (Figure C).
Ard, R., and Allshire, R.C. (2016). Transcription-coupled changes to chromatin underpin gene silencing by transcriptional interference. Nucleic Acids Res. 44, 10619–10630.
Shukla, M., Tong, P., White, S.A., Singh, P.P., Reid, A.M., Catania, S., Pidoux, A.L., Allshire, R.C. (2018) Centromeric DNA destabilizes H3 nucleosomes to promote CENP-A deposition during the cell cycle. Curr. Biol. 28:3924-3936.
Heyn, P., Logan, C.V., Fluteau, A., Challis, R.C., Auchynnikava, T., Martin, C.A., Marsh, J.A., Taglini, F., Kilanowski, F., Parry, D.A., Cormier-Daire, V., Fong, C.T., Gibson, K., Hwa, V., Ibáñez, L., Robertson, S.P., Sebastiani, G., Rappsilber, J., Allshire, R.C., Reijns, M.A.M., Dauber, A., Sproul, D., Jackson, A.P. (2019) Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 51:96-105.