Allshire Lab

 EPIGENETICS & SPECIALIZED CHROMATIN

Genomes are packaged as chromatin in nucleosomes composed of core histones (H2A/H2B/H3/H4).  Epigenetic processes, mediated by histone post-translational modifications, allow continued gene expression/repression in cell lineages.  Understanding how such ‘marks’ establish and propagate chromatin states is critical for specifying and maintaining distinct cell types.  Moreover, epigenetic states provide a source of phenotypic variation, independent of DNA sequence.

Lineage commitment and reprogramming of cell fate involves both chromatin-mediated shutdown and activation of elaborate transcription programmes. Specialised chromatin domains are therefore fundamentally important, but dissecting these epigenetic mechanisms remains challenging in mammals. Model organisms such as fission yeast are effective for uncovering important principles applicable across phyla.

Epigenetic heritability is an important property of both heterochromatin and CENP-A chromatin: once formed they can persist without initiating signals. Since debilitating disorders (i.e. Friedreich’s Ataxia, FSHD) result from aberrant heterochromatin-mediated gene silencing, it is important to understand events that promote and deter gene silencing. Moreover, stochastic gene silencing in response to environmental cues may trigger transgenerational inheritance of epigenetically-regulated traits. Functional CENP-A chromatin is assembled only at centromeres; chromosome missegregation and aneuploidy result from defective CENP-A and kinetochore assembly. Regulated CENP-A deposition prevents unstable chromosome formation by ensuring assembly of only one kinetochore per chromosome. Overexpression of CENP-A and its assembly factors is prevalent in various aggressive tumours where they may drive genome instability.

Our goal is to decipher conserved mechanisms that establish, maintain and regulate assembly of heterochromatin and CENP-A chromatin domains. We aim to provide provide insight into how heterochromatin forms on canonical pericentromere repeats. Heterochromatin may also silence genes throughout the genome, we are investigating how stochastic silencing might exert epigenetic influences on phenotype.  We also strive to understand how heterochromatin, spatial nuclear organisation and non-coding RNAPII transcription combine to mediate CENP-A incorporation at centromeres.

Trypanosome epigenetics: in collaboration with Keith Matthews we are investigating the nature and function of heterochromatin in the sleeping sickness parasite, Trypanosoma brucei.