Wellcome Senior Research Fellow
Adele Marston is a Wellcome Senior Research Fellow and Professor in Cell Biology at the University of Edinburgh. Her group aims to understand the origin of aneuploidy, particularly during meiosis, the cell division that generates eggs and sperm. The focus is to understand molecular mechanisms of chromosome segregation, primarily using yeast, together with a combination of genetics, biochemistry and microscopy. Adele obtained her PhD from the University of Oxford, in the lab of Jeff Errington, and carried out postdoctoral work with John Chant at Harvard University and Angelika Amon at MIT. In 2005 she moved to the Wellcome Centre for Cell Biology in Edinburgh to establish her independent research group as a Wellcome Research Career Development Fellow. In 2010 she obtained a Wellcome Senior Fellowship, renewed in 2015.
Orienting Chromosomes during Mitosis and Meiosis
Specialization of chromosome segregation mechanisms in meiosis
Meiosis generates gametes with half the parental genome through two consecutive chromosome segregation events, meiosis I and meiosis II. Meiotic errors are prevalent in humans, accounting for frequent miscarriages, birth defects and infertility. Our vision is to elucidate the molecular basis of the adaptations that sort chromosomes into gametes during meiosis. We use budding and fission yeast as general discovery tools, and Xenopus and mouse oocytes to uncover meiotic mechanisms in vertebrates. Using patient-donated oocytes and ovarian tissue, we address the relevance of our findings for human fertility.
Structural and functional organisation of pericentromeres
During meiosis, chromosomes undergo remarkable remodelling for transmission into gametes. Chromosomes are broken and reciprocally exchanged in prophase, specifically cohered at centromeres during meiosis I and permanently separated at meiosis II. Chromosome morphogenesis begins before S phase, when cohesion establishment links sister chromatids coupled to DNA replication. The cohesin complex is a major definer of chromosome structure, establishing intra and inter-sister chromatid linkages and providing the context for spatial control of homolog interactions. Our group revealed how chromosomes are structured for their segregation during mitosis. We established the region around the centromere, called the pericentromere, as a paradigm for chromosomal domain organisation. We discovered that cohesin is loaded at the centromere and that the borders of pericentromeres are marked by convergent genes that trap cohesin. This folds pericentromeres into a looped structure that is important for accurate chromosome segregation. Our current work is aimed at understanding how pericentromere structure is adapted during meiosis to suppress meiotic recombination and to accommodate the co-segregation of sister chromatids during meiosis I.
Specialization of meiotic kinetochores
Kinetochores link centromeric nucleosomes to microtubules for chromosome segregation. Our goal is to understand how the kinetochore is adapted to perform its meiosis-specific functions in suppression of meiotic recombination, directing the co-segregation of sister chromatids during meiosis I, and maintaining linkages between sister chromatids until meiosis II. Recently, we defined the proteomic landscape of yeast kinetochores and centromeric chromatin during meiosis, revealing extensive remodelling during prophase and meiosis I. We are now addressing the mechanism of kinetochore remodelling, as well as its functional importance. In many organisms, sister kinetochores are fused in meiosis I, while a lack of fusion in human oocytes may account for susceptibility to segregation errors and fertility problems. Ongoing work in Xenopus, mouse and human oocytes aims to test this hypothesis.
Borek WE, Vincenten N, Duro E, Makrantoni V, Spanos C, Sarangapani KK, de Lima Alves F, Kelly DA, Asbury CL, Rappsilber J and Marston AL. (2021) The proteomic landscape of centromeric chromatin reveals an essential role for the Ctf19CCAN complex in meiotic kinetochore assembly. Current Biology 31, 283-296.
Paldi F, Alver B, Robertson D, Schalbetter SA, Kerr A, Kelly D, Baxter J, Neale MJ and Marston AL (2020). Convergent genes shape budding yeast pericentromeres. Nature 582, 119-123.
Galander S, Barton RE*, Borek WE*, Spanos C, Kelly DA, Robertson D, Rappsilber J and Marston AL (2019) Reductional meiosis I chromosome segregation is established by coordination of key meiotic kinases. Developmental Cell 49, 526-541.
A. Whole genome Hi-C view showing chromosomal contacts of budding yeast arrested in mitotic metaphase.
B. The Mcm21 protein is required for kinetochore remodeling in yeast meiosis. Live cell imaging of kinetochore protein Mtw1-tdTomato in wild type and mcm21D cells.
C. Human metaphase II oocyte stained for tubulin (orange), DNA (blue) and shugoshin 2 (green).