Wellcome Principal Research Fellow
William Earnshaw moved to Edinburgh in 1996 as a Wellcome Principal Research Fellow, which he remains today. He graduated summa cum laude from Colby College in Waterville Maine in 1972, then completed a Ph.D. with Jonathan King at MIT in 1977 after a brief stint in the US Air Force. Postdoctoral training in Cambridge with Aaron Klug, Tony Crowther and Ron Laskey and in Geneva with Ulrich Laemmli was followed by 13 years at the Johns Hopkins School of Medicine. Throughout his career, his studies have focused on the packaging and segregation of chromosomes during cell division. Achievements of his team during his time in Edinburgh include identification of the chromosomal passenger complex, construction of the first human synthetic artificial chromosome and the use of multidisciplinary approaches to study the organisation and formation of vertebrate mitotic chromosomes. He has been elected to EMBO, the Royal Society of Edinburgh, the Academy of Medical Sciences and the Royal Society of London. He co-authors the textbook Cell Biology with Tom Pollard, Graham Johnson and Jennifer Lippincott-Schwartz (3rd edition published in 2017).
The role of non-histone proteins in chromosome structure and function during mitosis
In 2020/21, our research focused on structural transformations during mitotic chromosome formation, epigenetic regulation of kinetochore assembly/stability and the role of the chromosomal passenger complex (CPC) in regulating cell division. We spent most of 2020/21 at home analysing data, working on manuscripts, chewing fingernails and attending Zoom Journal Club and Lab Meetings (other brands are available, but we don’t use them). The Zoom format may persist after restrictions ease, as we have become quite comfortable with it.
Bill’s PRF renewal application was submitted 1 week before Scotland went into lockdown. Painstaking practice for written responses to the grants panel and subsequent negotiations with Wellcome about the final award were ultimately rewarded with success, providing a glimmer of light in this dark period. Bill and Elisa also spent many hours preparing for our return to the lab in July. For the foreseeable future we are limited to 5 people in the main lab at any one time. Thus, progress is impeded, but not completely blocked.
Underpinning most of our studies is Kumiko’s chemical-genetic system for obtaining highly synchronous entry of cultured cells into mitosis. We can now do biochemical analysis on processes that could only previously be studied by live-cell microscopy.
- We are writing up a comprehensive study of protein-DNA transactions during mitotic entry. This paper focuses on disassembly of the nucleus during very early prophase. This turned out to be unexpectedly interesting, in part because dramatic changes occur in the nucleolus long before any condensation of the DNA can be seen (see Figure).
- We are also preparing to publish our multidisciplinary study of interactions between major chromosome scaffold proteins during mitotic chromosome formation, a collaboration with the groups of Job Dekker, Leonid Mirny and Anton Goloborodko. We do the genetics, cell biology and imaging. They do Hi-C and polymer modelling, respectively.
- We continue to study the enigmatic and perplexing protein Ki-67 and the RNA/protein-rich mitotic chromosome periphery compartment (MCPC). Preliminary studies reveal that Ki-67 still has surprises in store for us and indicate that components of the mysterious MCPC may be essential for accurate chromosome segregation.
- Our work on mitotic chromosome segregation focuses on the formation of human artificial chromosomes (HACs). We discovered that major genome scrambling similar to chromothripsis often occurs at an early stage in HAC formation. Ongoing experiments aim to understand these early steps in HAC formation, and hopefully minimize the rearrangements. This is critical for planned efforts to construct synthetic human chromosomes which would be futile if chromosomes assembled at great effort and cost were scrambled when introduced into human cells.
Our work is supported by a Wellcome Principal Research Fellowship and by the Centre for Mammalian Synthetic Biology.
Papini, D., X. Fant, H. Ogawa, N. Desban, K. Samejima, O. Feizbakhsh, B. Askin, T. Ly, W.C. Earnshaw† & S. Ruchaud†. (2019). †equal corresponding authors. Plk1-dependent cell cycle-independent furrowing triggered by phosphomimetic mutations of the INCENP STD motif. J. CELL SCI. 132: jcs234401 PMID: 31601613; DOI: 10.1242/jcs.234401.
Martins*, N.M.C., F. Cisneros-Soberanis*, E. Pesenti*, N.Y. Kochanova, W.-H. Shang, T. Hori, T. Nagase, H. Kimura, V. Larionov, H. Masumoto, T. Fukagawa & W.C. Earnshaw. (2020). H3K9me3 maintenance on a Human Artificial Chromosome is required for segregation but not centromere epigenetic memory. J. CELL SCI. 133: JCS242610: PMID: 32576667; PMC7390644; DOI: 10.1242/jcs.242610.
Pesenti,E., M. Liskovykh, K. Okazaki, A. Mallozzi, C. Reid, M.A. Abad, A.A. Jeyaprakash, N. Kouprina, V. Larionov, H. Masumoto, W.C. Earnshaw. (2020) Analysis of Complex DNA Rearrangements During Early Stages of HAC Formation. ACS SYNTH BIOL. 9:3267-3287. PMID: 33289546; PMC7754191; DOI: 10.1021/acssynbio.0c00326.
A. tSNE map showing protein clusters that move away from DNA at various times during early mitosis.
B. The order of movement of the 6 clusters shown here. The left-most two clusters are highly enriched for proteins involved in pre-rRNA processing and leave the DNA before chromatin condensation is visible. Many of these proteins end up on the mitotic chromosome periphery. Nuclear pore proteins and proteins of the inner nuclear envelope are also early to move away from DNA.