Prof Brian McStay

Professor of Biochemistry
Wellcome Trust Investigator & EMBO member

Research interests

  • The organisation of ribosomal genes on human acrocentric chromosomes
  • Formation and organisation of the nucleolus in human cells

Research overview

Fig 1. Nucleolar organiser regions: genomic ‘dark matter’ requiring illumination. (see McStay 2016)

Nucleoli, sites of ribosome biogenesis and the largest structures in the human nucleus, form around nucleolar organiser regions (NORs) located on the short or p-arms of five different chromosomes referred to as acrocentric chromosomes (see McStay 2016). NORs comprise ribosomal genes (rDNA) arrays coding for the major RNA components of ribosomes. How multiple acrocentric p-arms gather together to form a nucleolus and how NORs partition within nucleoli are important but unanswered questions. Progress has been hampered by the inability to distinguish acrocentric p-arms from each other due to their shared DNA-sequences (Van Sluis et al 2019 and Floutsakou et al 2013), see also blog from the Genome Reference Consortium.

To circumvent this impasse, the McStay lab has developed powerful chromosome-engineering approaches on single human chromosomes held in mono-chromosomal somatic cell hybrids. These engineered chromosomes can then be reintroduced into human cells to test function in nucleolar formation (see Mangan and McStay 2021). Using this transformative technology and recently renewed funding from the SFI-HRB-Wellcome Research Partnership, we are currently addressing the following aims.

  • Characterise chromosomal requirements for formation of large multivalent nucleoli.
  • Identify factor(s) constraining NOR-territories (see Mangan and McStay 2021).
  • Explore cellular responses to rDNA DSBs using genome-edited human NORs (see Van Sluis and McStay 2015).
  • Construct a minimal NOR-bearing human chromosome by top-down chromosome-engineering.

Fig 2. A model for nucleolar organisation in normal growth conditions and under nucleolar stresses (see Mangan and McStay 2021)

Additionally we aim to  explore tantalising links between rDNA genome-stability and cell-ageing. This work has added significance as nucleoli represent an important paradigm for understanding human genome organisation. This work is supported by an Investigator Award (223049/Z/21/Z) from the SFI-HRB-Wellcome Trust Biomedical Research Partnership.

Selected publications

  • Mangan, H. and McStay, B. (2021). Human nucleoli comprise multiple constrained territories, tethered to individual chromosomes. Genes Dev;35-483-488
  • van Sluis, M., van Vuuren, C., Mangan, H., and McStay, B. (2020). NORs on human acrocentric chromosome p-arms are active by default and can associate with nucleoli independently of rDNA. Proc Natl Acad Sci U S A 117, 10368-10377
  • van Sluis, M., Gailin, M.O., McCarter, J.G.W., Mangan, H., Grob, A., and McStay, B. (2019). Human NORs, comprising rDNA arrays and functionally conserved distal elements, are located within dynamic chromosomal regions. Genes Dev 33, 1688-1701
  • McStay, B. (2016). Nucleolar organizer regions: genomic 'dark matter' requiring illumination. Genes Dev 30, 1598-1610
  • van Sluis, M., and McStay, B. (2015). A localized nucleolar DNA damage response facilitates recruitment of the homology-directed repair machinery independent of cell cycle stage. Genes Dev 29, 1151-1163
  • Grob, A., Colleran, C., and McStay, B. (2014). Construction of synthetic nucleoli in human cells reveals how a major functional nuclear domain is formed and propagated through cell division. Genes Dev 28, 220-230
  • Floutsakou, I., Agrawal, S., Nguyen, T.T., Seoighe, C., Ganley, A.R., and McStay, B. (2013). The shared genomic architecture of human nucleolar organizer regions. Genome Res 23, 2003-2012