Robin Allshire

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.

Lab members

Tatsiana Auchynnikava, Roberta Carloni, Tadhg Devlin, Andreas Fellas, Elisabeth Gaberdiel, Dominik Hoelper, Marcel Lafos, Nitobe London, Sunil Nahata, Alison Pidoux, Severina Pociunaite, Desislava Staneva, Manu Shukla, Sito Torres-Garcia, Sharon White, Weifang Wu, Imtiyaz Yaseen, Rebecca Yeboah

A simple overview of research in the Allshire Lab - Research in a Nutshell Videos


Epigenetic inheritance: establishment and transmission of specialised chromatin domains

Chromosomal DNA wraps around nucleosomes containing core histones (H3/H4/H2A/H2B).  At centromeres however, a specific histone H3 variant, CENP-A, replaces histone H3 to form specialized CENP-A nucleosomes. CENP-A chromatin is critical for chromosome segregation machinery assembly (kinetochores) at these specific chromosomal locations. Kinetochores are flanked by histone H3 lysine 9 methylation (H3K9me)-dependent heterochromatin.
Our goal is to decipher conserved mechanisms that establish, maintain and regulate heterochromatin and CENP-A chromatin domain assembly. Heterochromatin is required for CENP-A chromatin establishment 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?

H3K9me-dependent heterochromatin renders embedded genes transcriptionally silent. Fission yeast 
(Schizosaccharomyces pombe) H3K9me-dependent heterochromatin can be transmitted through cell division provided the counteracting demethylase Epe1 is absent. Can heterochromatin heritability allow wild-type cells under certain conditions to acquire epimutations, which influence phenotype through unstable gene silencing rather than DNA mutation? We have discovered that heterochromatin-dependent epimutants resistant to caffeine can arise in fission yeast (Torres-Garcia et al. 2020). Isolates with unstable resistance have distinct heterochromatin islands with reduced expression of underlying genes, including some whose mutation confers caffeine resistance (Figure A). Our analyses suggest that epigenetic processes promote phenotypic plasticity, allowing wild-type cells to adapt to unfavourable environments without genetic alteration. Isolates with unstable caffeine resistance show cross-resistance to fungicides (Figure B), suggesting that related heterochromatin-dependent processes may contribute to resistance in plant and human fungal pathogens. Such epimutations provide a bet-hedging strategy allowing cells to adapt transiently to insults while remaining genetically wild-type (Figure C).

It is not known why heterochromatin has a distinct architecture on mitotic chromosomes. We find that large regions of fission yeast DNA inserted into mammalian chromosomes assemble H3K9me-dependent heterochromatin which adopts a mitotic organisation distinct from surrounding host chromosome regions (Fitz-James et al. 2020). Heterochromatin assembled on this inserted fission yeast DNA alters chromatin loop size relative to flanking euchromatic host chromatin 
(Figure D). Thus, altered loop size likely contributes to the distinct appearance of heterochromatin (Figure E).

Selected publications:

Singh, P.P., Shukla, M., White, S.A., Lafos, M., Tong, P., Auchynnikava, T., Spanos, C., Rappsilber, J., Pidoux, A.L., and Allshire, R.C. (2020). Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin. Genes Dev 34, 226–238.

Fitz-James, M.H., Tong, P., Pidoux, A.L., Ozadam, H., Yang, L., White, S.A., Dekker, J., Allshire, R.C. (2020). Large domains of heterochromatin direct the formation of short mitotic chromosome loops. Elife 9, e57212. doi: 10.7554/eLife.57212.

Torres-Garcia, S., Yaseen, I., Shukla, M., Audergon, P.N.C.B., White, S.A., Pidoux, A.L., Allshire, R.C. (2020). Epigenetic gene silencing by heterochromatin primes fungal resistance. Nature  , 453-458. doi: 10.1038/s41586-020-2706-x. 
 

A. Unstable caffeine resistant epimutants UR-1 and UR-2 exhibit novel islands of H3K9me-dependent heterochromatin compared to wild-type cells (wt).
B. UR-1 and UR-2 caffeine resistant (CAF) epimutants are cross-resistant to clinical (CLT, Clotrimazole; FLC, Fluconazole) and agricultural (TEB, Tebuconazole) fungicides used to treat human and crop-plant fungal infections, respectively.
C. Model. Resistant isolates arise after lethal insult exposure. Resistance can be mediated by changes in DNA (resistant mutants) or reversible, heterochromatin-based epimutations (resistant epimutants). Upon withdrawal of insult epimutants lose ectopic heterochromatin islands, resistance, reverting to wild-type (sensitive phenotype). In contrast genetic mutants continue to exhibit the mutant resistance phenotype.
D. Large inserts of fission yeast DNA in mammalian chromosomes exhibit an unusual mitotic chromosome structure associated with H3K9me-dependent heterochromatin formation. Hi-C analyses demonstrate more frequent contacts per kb over the fission yeast insert compare to flanking mouse chromatin.
E. Model. A higher ratio of condensin to chromatin over fission yeast DNA assembled in heterochromatin results in more contacts and less chromatin per unit length and consequently, reduced mitotic chromosome width.