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Bill Earnshaw


Daniel Booth, Mar Carmena, Takashi Ideue, Oscar Molina, Melpomeni Platani, Jan Ruppert, Itaru Samejima, Kumiko Samejima, Giulia Vargiu, Alisa Zhiteneva
Earnshaw Lab website

The role of non-histone proteins in chromosome structure and function during mitosis

Bill gives a brief overview of his research.

The research from our laboratory focuses on three main aims.
1. Making the mitotic chromosome: How do mitotic chromosomes condense, and what is the role of histones and non-histone proteins in shaping them?
2. Segregating the chromosomes: How are centromere specification and kinetochore assembly controlled epigenetically?
3. Controlling the process: How does the chromosomal passenger complex (CPC) regulate chromosome segregation?

Although mitotic chromosomes were discovered in the 19th century, we still do not understand their organization or how they are formed. Our studies in this area combine structural analysis of individual protein subcomplexes by conventional and super-resolution light microscopy with cross-linking and mass spectrometry (CLMS) to study individual components. We have developed methods to allow cells to enter mitosis with near perfect synchrony and are using those cells as a source of isolated chromosomes for proteomic characterization and detailed modeling of the chromatin folding pattern by Hi-C analysis. 

Studies of chromosome segregation have focused in two areas: whole proteome analysis to examine functional relationships between kinetochore proteins, and a synthetic biology approach to examine the interplay between chromatin modifications and transcription in establishing a chromatin environment supportive for kinetochore assembly and maintenance. We prefer to describe pathways of epigenetic regulation as follows:
Editor —> Mark —> Reader —> Chromatin state. We are conducting a series of studies targeting artificial editors (which make or remove marks) to the centromere of a synthetic human artificial chromosome to create defined chromatin states, and then determining their effects on centromere stability and function. Moving beyond the synthetic artificial chromosome, these studies are now being expanded into PREditOR (protein reading and editing of residues), a synthetic biology approach to using diverse mark-reader pairs to manipulate cellular signalling pathways.

Our studies of mitotic regulation have led us to examine the mechanism of Aurora B kinase activation in the chromosome passenger complex – a key regulator of mitotic transitions. We are also exploring a new approach looking at the role of mTor kinase in regulating the activation of key mitotic kinases at centrosomes. Our work is supported by a Wellcome Trust Principal Research Fellowship to Bill Earnshaw, which was renewed this year for an additional 5-year term.

Selected publications:

Platani, M., L. Trinkle-Mulcahy, M. Porter, A.A. Jeyaprakash and W.C. Earnshaw. (2015). Mio depletion links mTOR regulation to Aurora A and Plk1 activation at mitotic centrosomes. J. Cell Biol. 210: 45-62. PMID: 26124292; PMC4494011; DOI: 10.1083/jcb.201410001
Papini, D., L. Langemeyer, M.A. Abad, A. Kerr, I. Samejima, P.A. Eyers, A.A. Jeyaprakash, J.M.G. Higgins, F.A. Barr and W.C. Earnshaw. (2015). TD-60 links RalA GTPase function to the CPC in mitosis. NATURE COMMS. 6: 7678. PMID: 26158537; PMC4510650; DOI: 10.1038/ncomms8678.
Samejima, I. C. Spanos, F. de Lima Alves, T. Hori, M. Perpelescu, J. Zou, J. Rappsilber, T. Fukagawa and W.C. Earnshaw. (2015). Whole proteome genetic analysis of dependencies in assembly of a vertebrate kinetochore. J. Cell Biol. 211:1141-1156. PMID: 26668330; PMC4687880; DOI: 10.1083/
jcb.201508072. (featured in “In This Issue” - J. Cell Biol. 211:1098; and “Research Highlights” Nature Reviews Mol. Cell Biol. 17:66, 2016, doi:10.1038/nrm.2015.30)

Genetic proteomics defines an interaction network for vertebrate kinetochore proteins based on correlation of the behaviour of the entire mitotic chromosome proteome when a number of different genes encoding kinetochore proteins are inactivated.