Research

Our goal is to understand the fundamental mechanisms by which cells reproduce themselves and transmit their genome to the next generation through mitosis and meiosis.

Mitosis and meiosis

Mitosis generates daughter cells with the identical number of chromosomes to the parental cell. Meiosis produces gametes such as egg or sperm, with half the DNA content to the parental cell.  

Illustration of mitosis and meiosis in budding yeast

Aneuploidy and disease

Errors in the segregation of chromosomes during cell division produce cells with the wrong number of chromosomes, known as aneuploidy. Cancer cells are typically aneuploid and aneuploid gametes cause birth defects, miscarriages and infertility. We aim to understand the origin of these chromosome abnormalities by dissecting the fundamental mechanisms of chromosome segregation. Human eggs are particularly prone to aneuploidy, especially as women age. A key priority of our research is to understand the underlying mechanisms, for which an understanding of the basic biology is essential.

Our Approach

We take a multi-disciplinary approach, employing the most appropriate tools, technology and model systems to address the major outstanding research questions. Current model systems include budding and fission yeast, as well as mouse and frog oocytes. We are also working with an IVF clinic to understand the relevance of our discoveries for human infertility. We use methods ranging from genetics, NGS DNA sequencing-based approaches (Hi-C, ChIP-Seq etc.), biochemistry, proteomics and super-resolution microscopy.

 

Cohesin localization along budding yeast chromosome V by chromatin immunoprecipitation

Specific aims

1. How does the structural organisation of pericentromeres ensure accurate chromosome segregation?

Chromosome segregation requires their capture by microtubules via a large structure called the kinetochore, which assembles at a specific location on the chromosome, called the centromere. The chromosomal region surrounding the centromere is called the pericentromere. We found that budding yeast pericentromeres are folded into a multi-looped structure by the action of the cohesin motor. Centromeres and convergent genes at pericentromere borders form the base of the loops and define their structure by positioning cohesin. This provided evidence that the linear order of transcription units defines chromosome structure, with functional consequences for chromosome transmission. We are now investigating how this structure is “read” by a protein known as shugoshin.

Illustration of biorientation during mitosis

2. How are kinetochores adapted for meiosis?

During the first meiotic division, uniquely, the maternal and paternal chromosomes are segregated, while the sister chromatids stay together. This requires that sister kinetochores co-segregate in meiosis I but only segregate away from each other at meiosis II. We are studying the modifications to kinetochores that allow this specialized behaviour. Importantly, the distance between sister kinetochores is increased in oocytes from older women so understanding the molecular basis of sister kinetochore co-orientation is an important priority.

Illustration of kinetochore adaptions in meiosis in budding yeast

3. How is cell cycle regulation modified to orchestrate meiotic chromosome behaviour?

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. We aim to uncover how meiotic cohesion is established, determine how cohesin spatially and functionally structures meiotic chromosomes and identify the cell cycle controls which ensure that chromosome morphogenesis is coordinated with developmental differentiation.

Illustration of Chromosome morphogensis in meiosis

4. What is the origin of aneuploidy in human meiosis and early mitosis?

We are analysing chromosome segregation mechanisms during the first and second meiotic divisions of the human oocyte as well as the early cleavage divisions of human embryos. We aim to define the molecular features of human meiotic kinetochores that could explain the high incidence of aneuploidy and begin to correlate aberrant kinetochore behaviour with specific changes in molecular composition and structure, and with donor characteristics such as maternal age. In the long term, we aim to provide patients with a better understanding of the molecular deficits that underlie infertility. This is part of an exciting collaboration with colleagues at the Universities of Warwick (Andrew McAinsh, Geraldine Hartshorne and Nigel Burroughs) and Edinburgh (Richard Anderson and Evelyn Telfer).

Illustration of meiosis in mammalian oocytes

This article was published on