Every dividing cell must thread its chromosomes onto a microscopic protein machine called the kinetochore, and this project investigates how cells mark the correct spot for that machine to assemble. The problem is that the DNA sequences at these assembly sites vary wildly between species, yet the cell somehow recognises them across generations. This research aims to uncover the fundamental signals—whether from the DNA itself, its associated RNA, or the act of transcription—that tell the cell where to build the kinetochore and where to silence repetitive DNA. It also asks whether the cell’s internal geography, specifically positioning near the nuclear wall, strengthens these specialised chromatin domains. This is fundamental science. There is no immediate medical or industrial application. However, errors in chromosome segregation cause miscarriages, birth defects, and cancers. Understanding how cells reliably mark and transmit these essential assembly points could, in the long term, illuminate why those errors occur. Past work on similar chromatin mechanisms in yeast has already revealed principles that govern gene silencing and genome stability across all complex life.
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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.
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