Epigenetic inheritance: establishment and transmission of specialised chromatin domains (360G-Wellcome-200885_Z_16_Z)

Specialized chromatin domains provide platforms that mediate fundamental cell and developmental functions. The histone H3-variant CENP-A chromatin directs assembly of kinetochores at specific chromosomal locations to enable accurate chromosome segregation. Heterochromatin renders potentially harmful repetitive elements inert and silences genes during development. Regional fission yeast centromeres provide an excellent paradigm for unwieldy metazoan centromeres. Our analyses indicate that H3K9-methylation-dependent heterochromatin and CENP-A assemble upon non-conserved elements at centromeres whose chromosomal location is preserved in related Schizosaccharomyces species. My predominant goal is to understand the conserved signals and mechanisms that distinguish these non-conserved centromere sequences from other genomic loci, as well as the epigenetic mechanisms that result in the establishment of heterochromatin and CENP-A chromatin, and their stable mitotic and transgenerational transmission. I aim to determine: 1. How specific signals associated with centromere DNA, RNA, chromatin and RNAPII transcription direct assembly and maintenance of heterochromatin and CENP-A specialised chromatin domains. 2. The influence that positioning at the nuclear periphery exerts on heterochromatin domain robustness and the establishment of CENP-A chromatin on adjacent centromere DNA. 3. The potential for sporadic heterochromatin formation across the genome to generate phenotypic heterogeneity in genetically identical wild-type cells thereby increasing adaptability to environmental changes.