Faculty of Medical Sciences

Staff Profile

Professor Jonathan Higgins

Professor of Eukaryotic Molecular Cell Biology and Deputy Dean of Research and Innovation

Background

Education:

1987-1991     BA, Biochemistry, University of Oxford

1991-1995     DPhil, University of Oxford

Postdoctoral training:

1995-1997     Research Fellow in Medicine, Brigham and Women's Hospital, Harvard Medical School, USA

Previous Appointments:

1997-2002      Instructor in Medicine, Brigham and Women's Hospital, Harvard Medical School, USA

2003-2014      Assistant Professor of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA

2003-2014      Member, Cancer Cell Biology Program, Dana-Farber/Harvard Cancer Center, USA

2006-2014      Member, Biological and Biomedical Sciences Graduate Program, Harvard Medical School, USA

Funding

I currently hold a Wellcome Trust Investigator Award and a Royal Society Wolfson Research Merit Award. Our work is also funded by the BBSRC and, previously, by the National Institutes of Health (USA), the American Cancer Society, the Leukemia and Lymphoma Society, and the Association for International Cancer Research/Worldwide Cancer Research.

Google Scholar: Click here.

Research

Our laboratory focuses on cell division, a process that requires a dramatic and highly orchestrated change in cell structure, including the condensation of chromosomes, their alignment on a bipolar spindle, the synchronous movement of exactly half of the chromosomes to opposite poles of the cell, and then cytokinesis (dividing the cell into two).

To accomplish cell division with high fidelity requires tight control of chromosome structure, including the displacement of proteins that might hinder chromosome segregation, and the recruitment of proteins that allow the chromosomes to condense and be “bi-oriented” on the spindle. Through all of this change, the cell also retains markers (“bookmarks”) on chromosomes that can “remember” whether genes are active or inactive so that they can be returned to their original states once cell division is complete. These events must be precisely controlled in location and timing. Our laboratory studies these control mechanisms. In particular, we study how chromatin modifications help determine where and when key regulatory factors can bind to chromosomes.

We are particularly interested in how histone kinases such as Haspin and Aurora B control cell division in human cells, how this process contributes to the generation of cancer and birth defects, and how it can be exploited for disease therapy. In the future, we aim to determine the roles of additional histone modifications in mitosis, to explore their functions in meiosis, and to develop a genome-wide understanding of how these marks are deposited to regulate both chromosome segregation and the inheritance of epigenetic information during cell division.

We are also part of the Cell Division Biology Group that includes other laboratories working on various aspects of eukaryotic cell division including the mitotic checkpoint, chromosome segregation in meiosis, the structure and function of the synaptonemal complex, and asymmetric cell division.

Teaching


MMB8008: Cell Cycle Control and Signalling in Health and Disease

CMB3000: Undergraduate Research Projects

CMB4099: MSci Research Projects


Publications

  • Seibert M, Krüger M, Watson NA, Sen O, Daum JR, Slotman JA, Braun T, Houtsmuller AB, Gorbsky GJ, Jacob R, Kracht M, Higgins JMG, Schmitz ML. CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation. Journal of Cell Biology 2019, 218(4), 1164–1181.
  • Levasseur MD, Thomas C, Davies OR, Higgins JMG, Madgwick S. Aneuploidy in oocytes is prevented by sustained CDK1 activity through degron masking in cyclin B1. Developmental Cell 2019, 48, 1-18.
  • Sen O, Saurin AT, Higgins JMG. The live cell DNA stain SiR-Hoechst induces DNA damage responses and impairs cell cycle progression. Scientific Reports 2018, 8, 7898.
  • Watson NA, Higgins JMG. Histone Kinases and Phosphatases. In: Binda O; Fernandez-Zapico M, ed. Chromatin Signaling and Diseases. Waltham, MA: Elsevier Inc, 2016, pp.75–94.
  • Higgins JMG, Prendergast L. Mitotic Mysteries: The Case of HP1. Developmental Cell 2016, 36(5), 477-478.
  • Pores Fernando AT, Andrabi S, Cizmecioglu O, Zhu C, Livingston DM, Higgins JMG, Schaffhausen BS, Roberts TM. Polyoma small T antigen triggers cell death via mitotic catastrophe. Oncogene 2015, 34(19), 2483-2492.
  • Papini D, Langemeyer L, Abad MA, Kerr A, Samejima I, Eyers PA, Jeyaprakash AA, Higgins JMG, Barr FA, Earnshaw WC. TD-60 links RalA GTPase function to the CPC in mitosis. Nature Communications 2015, 6, 7678.
  • Hadley GA, Higgins JMG. Integrin αEβ7: molecular features and functional significance in the immune system. In: I Domain Integrins. Dordrecht: Springer, 2014, pp.97-110.
  • Zhou L, Tian X, Zhu C, Wang F, Higgins JMG. Polo-like kinase-1 triggers histone phosphorylation by Haspin in mitosis. EMBO Reports 2014, 15, 273-281.
  • Higgins JMG. Chromosome Segregation: Learning to let go. Current Biology 2013, 23(19), R883-R885.
  • Wang F, Higgins JMG. Histone Modifications and Mitosis: Countermarks, Landmarks and Bookmarks. Trends in Cell Biology 2013, 23(4), 175-184.
  • Higgins JMG, Herbert M. Nucleosome Assembly Proteins Get SET to Defeat the Guardian of Chromosome Cohesion. PLoS Genetics 2013, 9, e1003829.
  • Wang F, Ulyanova NP, Daum JR, Patnaik D, Kateneva AV, Gorbsky GJ, Higgins JMG. Haspin inhibitors reveal centromeric functions of Aurora B in chromosome segregation. Journal of Cell Biology 2012, 199(2), 251-268.
  • Niedzialkowska E, Wang F, Porebski PJ, Minor W, Higgins JMG, Stukenberg PT. Molecular basis for phosphospecific recognition of histone H3 tails by Survivin paralogues at inner centromeres. Molecular Biology of the Cell 2012, 23(8), 1457-1466.
  • Cuny GD, Ulyanova NP, Patnaik D, Liu JF, Lin H, Auerbach K, Ray SS, Xian J, Glicksman MA, Stein RL, Higgins JMG. Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors. Bioorganic and Medicinal Chemistry Letters 2012, 22(5), 2015-2019.
  • Wang F, Ulyanova NP, van der Waal MS, Patnaik D, Lens SM, Higgins JMG. A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in Mitosis. Current Biology 2011, 21(12), 1061-1069.
  • Czakai K, Müller K, Pepe G, Mosesso P, Jeanclos E, Gohla A, Patnaik D, Dekant W, Higgins JMG, Mally A. Perturbation of mitosis through inhibition of histone acetyltransferases: the key to ochratoxin A toxicity and carcinogenicity?. Toxicological Sciences 2011, 122(2), 317-329.
  • Varier RA, Outchkourov NS, de Graaf P, van Schaik FMA, Ensing HJL, Wang F, Higgins JMG, Kops GJPL, Timmers HThM. A phospho/methyl switch at histone H3 regulates TFIID association with mitotic chromosomes. EMBO Journal 2010, 29, 3967-78.
  • Higgins JMG. Haspin: a newly discovered regulator of mitotic chromosome behavior. Chromosoma 2010, 119, 137–147.
  • Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JM. Histone H3 Thr-3 Phosphorylation by Haspin Positions Aurora B at Centromeres in Mitosis. Science 2010, 330(6001), 231-235.
  • Cuny GD, Robin M, Ulyanova NP, Patnaik D, Pique V, Casano G, Liu JF, Xian J, Glicksman MA, Stein RL, Higgins JMG. Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. Bioorganic and Medicinal Chemistry Letters 2010, 20, 3491-3494.
  • Kateneva AV, Higgins JMG. Shugoshin and PP2A: collaborating to keep chromosomes connected. Developmental Cell 2009, 17, 303-305.
  • Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray JW, Higgins JMG, Knapp S. Structure and functional characterization of the atypical human kinase haspin. Proceedings of the National Academy of Sciences of the United States of America 2009, 106(48), 20198–20203.
  • Dai J, Kateneva AV, Higgins JMG. Studies of Haspin-depleted cells reveal that spindle-pole integrity requires chromosome cohesion. Journal of Cell Science 2009, 122, 4168-4176.
  • Higgins JMG. Haspin. UCSD-Nature Molecule Pages 2008, doi:10.1038/mp.a003132.01.
  • Patnaik D, Xian J, Glicksman MA, Cuny GD, Stein RL, Higgins JMG. Identification of Small Molecule Inhibitors of the Mitotic Kinase Haspin by High Throughput Screening using a Homogeneous Time-Resolved Fluorescence Resonance Energy Transfer Assay. Journal of Biomolecular Screening 2008, 13, 1025-1034.
  • Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JMG, Potier N, Scheidtmann KH, Buettner R, Schüle R. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nature Cell Biology 2008, 10, 53-60.
  • Parisini E, Higgins JMG, Liu JH, Brenner MB, Wang JH. The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism. Journal of Molecular Biology 2007, 373, 401-411.
  • Dai J, Sullivan BA, Higgins JMG. Regulation of mitotic chromosome cohesion by Haspin and Aurora B. Developmental Cell 2006, 11, 741-750.
  • Kiener HP, Stipp CS, Allen PG, Higgins JMG, Brenner MB. The cadherin-11 cytoplasmic juxta-membrane domain promotes α-catenin turnover at adherens junctions and intercellular motility. Molecular Biology of the Cell 2006, 17, 2366-76.
  • Dai J, Higgins JMG. Haspin: A Mitotic Histone Kinase Required for Metaphase Chromosome Alignment. Cell Cycle 2005, 4, 665-668.
  • Dai J, Sultan S, Taylor SS, Higgins JMG. The kinase haspin is required for mitotic histone H3 threonine-3 phosphorylation and normal metaphase chromosome alignment. Genes and Development 2005, 19, 472-488.
  • Sacks DB, Higgins JMG. Cadherin Signaling. In: Lennarz, WJ; Lane, MD, ed. Encyclopedia of Biological Chemistry. Academic Press/Elsevier Science, 2004.
  • Valencia X, Higgins JMG, Kiener HP, Lee DM, Pobrebarac TA, Dascher CC, Mizoguchi E, Simmons B, Patel DD, Bhan AK, Brenner MB. Cadherin-11 provides specific cellular between fibroblast-like synoviocytes. Journal of Experimental Medicine 2004, 200, 1673-1679.
  • Hintermann E, Yang N, O'Sullivan D, Higgins JMG, Quaranta V. Integrin α6β4/erbB2 complex inhibits haptotaxis by upregulating E-cadherin cell-cell junctions in keratinocytes. Journal of Biological Chemistry 2004, 280, 8004-80015.
  • Higgins JMG. Structure, function and evolution of haspin and haspin-related proteins, a distinctive group of eukaryotic proteins kinases. Cellular and Molecular Life Sciences 2003, 60, 446-462.
  • Kilshaw PJ, Higgins JMG. Alpha E: no more rejection?. Journal of Experimental Medicine 2002, 196, 873-876.
  • Kilshaw PJ, Higgins JMG. Integrin αEβ7: molecular features and functional significance in the immune system. In: Gullberg, D, ed. I-domains in integrins. Georgetown, TX: Landes Bioscience/Springer, 2002.
  • Higgins JMG. Haspin-like proteins, a new family of evolutionarily conserved putative eukaryotic protein kinases. Protein Science 2001, 10, 1677-1684.
  • Strauch UG, Mueller RC, Li XY, Cernadas M, Higgins JMG, Binion DG, Parker CM. Integrin αE(CD103)β7 mediates adhesion to intestinal microvascular endothelial cell lines via an E-cadherin independent mechanism. Journal of Immunology 2001, 166, 3506-3514.
  • Bono P, Rubin K, Higgins JMG, Hynes RO. Layilin, a novel integral membrane protein, is a hyaluronan receptor. Molecular Biology of the Cell 2001, 12, 891-900.
  • Higgins JMG. The Haspin gene: location in an intron of the Integrin αE gene, associated transcription of an Integrin αE-derived RNA and expression in diploid as well as haploid cells. Gene 2001, 267, 55-69.
  • Taraszka KS, Higgins JMG, Tan K, Mandelbrot DA, Wang JH, Brenner MB. Molecular Basis for Leukocyte Integrin αEβ7 Adhesion to Epithelial (E)-Cadherin. Journal of Experimental Medicine 2000, 191, 1555-1567.
  • Higgins JMG, Cernadas M, Tan K, Irie A, Wang JH, Takada Y, Brenner MB. The Role of α and β Chains in Ligand Recognition by β7 Integrins. Journal of Biological Chemistry 2000, 275, 25652-25664.
  • Agace WW, Higgins JMG, Sadasivan B, Brenner MB, Parker CM. T-lymphocyte-epithelial-cell interactions: integrin αE(CD103)β7, LEEP-CAM and chemokines. Current Opinion in Cell Biology 2000, 12(5), 563-568.
  • Li Z, Kim SH, Higgins JMG, Brenner MB, Sacks D. IQGAP1 and Calmodulin Modulate E-cadherin Function. Journal of Biological Chemistry 1999, 274, 37885-37892.
  • Higgins JMG, Mandelbrot DA, Shaw SK, Russell GJ, Murphy EA, Chen YT, Nelson WJ, Parker CM, Brenner MB. Direct and regulated interaction of integrin αEβ7 with E-cadherin. Journal of Cell Biology 1998, 40, 197-210.
  • Higgins JMG, Wiedemann H, Timpl R, Reid KBM. Characterization of Mutant Forms of Recombinant Human Properdin Lacking Single Thrombospondin Type I Repeats: Identification of modules important for function. Journal of Immunology 1995, 155, 5777-5785.
  • Nolan KF, Kaluz S, Higgins JMG, Goundis D, Reid KBM. Characterization of the human properdin gene. Biochemical Journal 1992, 287, 291-297.