BBS Faculty Member - Jonathan Higgins

Jonathan Higgins

Department of Medicine
Scholar of the Leukemia and Lymphoma Society

Brigham and Women's Hospital
Smith Building, Room 538A
1 Jimmy Fund Way
Boston, MA 02115
Tel: 617-525-1101
Fax: 617-525-1010
Email: jhiggins@rics.bwh.harvard.edu



Accurate chromosome segregation during cell division requires dramatic changes in chromatin structure and microtubule organization and is crucial to prevent genome instability that can contribute to cancer and cause birth defects. Our research focuses on the factors that are responsible for regulation of these changes, with emphasis on the role of kinases and histone modifications in mitosis.

We have found that mitotic phosphorylation of histone H3 at threonine-3 by the kinase Haspin creates a direct binding site for the Aurora B complex at centromeres. This provides the first clear example of how histone modifications provide spatial and temporal cues to position regulatory proteins on chromatin during mitosis to allow chromosome segregation. Haspin also has a less well-understood role in maintaining cohesion between sister chromatids until they are separated at anaphase.

Current interests include:
1. Understanding how Haspin and Aurora B co-operate at centromeres to allow accurate chromosome segregation.
2. Determining the mechanism by which Haspin regulates sister chromatid cohesion, identifying Haspin binding proteins, and determining how Haspin activity is regulated.
3. Using selective small molecule inhibitors of Haspin we have developed to uncover the roles of Haspin in mitosis in ways that are not possible with gene deletion and RNAi. These studies will also help determine if Haspin is a viable drug target in cancer.
4. Determining the functions of other histone modifications in mitosis.
5. Understanding mechanisms by which microtubule formation at centromeres is controlled, and how this influences mitotic spindle structure.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Wang F, Dai J, Daum JR, Niedzialkowska E, Banerjee B, Stukenberg PT, Gorbsky GJ, Higgins JMG. Histone H3 Thr-3 phosphorylation by Haspin positions Aurora B at centromeres in mitosis. Science 2010, 330:231-235

Eswaran J, Patnaik D, Filippakopoulos P, Wang F, Stein RL, Murray J, Higgins JMG,* Knapp S.* Structure and functional characterization of the atypical human kinase Haspin.
Proc. Natl. Acad. Sci. USA 2009, 106:20198-20203

Dai J, Sullivan BA, Higgins JMG. Regulation of mitotic chromosome cohesion by Haspin and Aurora B.
Dev. Cell 2006, 11:741-750

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 Dev. 2005, 19:472-88



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