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
Our goal is to understand the molecular mechanisms that ensure the accurate transmission of chromosomes to daughter cells during cell division. Errors in chromosome segregation generate cells with the wrong number of chromosomes, a condition called aneuploidy. Aneuploid somatic cells arise due to errors in mitosis and are associated with cancer. Aneuploid gametes are generated from erroneous meiosis and cause miscarriages, infertility and birth defects. Mitosis and meiosis are highly conserved, so we use yeast to uncover fundamental mechanisms of chromosome segregation. We also work with human oocytes to understand how the mechanisms we identify impact human fertility.
Structural and functional organisation of pericentromeres
This year we revealed how chromosomes are structured for their segregation during mitosis. Our group has established the region around the centromere, called the pericentromere, as a paradigm for chromosomal domain organisation. Pericentromeres are highly enriched in the chromosome-organising complex, cohesin, and this is important for accurate chromosome segregation. We found that pericentromeric cohesin enrichment is achieved by targeted cohesin loading at centromeres through a direct, phosphorylation-dependent interaction between the cohesin loader complex and the kinetochore. Recently, we discovered that the borders of pericentromeres are marked by convergent genes that trap cohesin. We found that the pericentromere is folded into a multi-looped structure with centromeres acting as strong insulators. Centromeres and convergent genes at pericentromere borders form the base of the loops and define their structure by positioning cohesin. In the absence of these loops, chromosome segregation was impaired. This provides evidence that the linear order of transcription units defines chromosome structure, with functional consequences for chromosome transmission.
Specialization of meiotic kinetochores
We are also studying the molecular basis of the meiosis-specific adaptations to the chromosome segregation machinery that ensure production of viable gametes. During the first meiotic division, uniquely, the maternal and paternal chromosomes are segregated, while the sister chromatids stay together. Our work revealed that a master meiosis I-specific regulator modulates the activity of multiple kinases to establish these modifications, essentially converting mitosis into meiosis. We also made progress in understanding how sister chromatids stay together during meiosis I. We determined how the monopolin complex, which cross-links sister kinetochores to fuse them, associates with kinetochores. This is a first step towards understanding the major question of how sister chromatids co-segregate during meiosis I, the basis of Mendelian inheritance.
Our ongoing and future focus is to understand molecular mechanisms that specialize the chromosome segregation machinery for meiosis, both in yeast and human oocytes.
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.
Hinshaw SM, Makrantoni V, Harrison SC and Marston AL (2017) The Kinetochore Receptor for the Cohesin Loading Complex. Cell 171, 72-84.
Plowman R, Singh N, Tromer E, Payan A, Duro E, Spanos C, Rappsilber J, Snel B, Kops GJPL, Corbett KD and Marston AL (2019) The molecular basis for monopolin recruitment to the kinetochore. Chromosoma 128, 331-354.
A. Pericentromere structure in mitosis. Hi-C analysis of budding yeast pericentromeres from metaphase-arrested cells in
the absence (no tension) or presence (tension) of microtubules. Mirrored pileups of contacts 25kb surrounding all 16
yeast centromeres are shown, with schematics below.
B. Metaphase-arrested budding yeast cells. Spindle pole bodies are labelled in red and the anaphase marker, Cdc14, is
labelled in green.
C. Human oocyte at metaphase II. The oolemma and chromosomes are stained blue and green, respectively.