Heads of Laboratories
Laboratory of Chromosome and Cell Biology
During mitosis, a full set of chromosomes must be equally transmitted to the offspring of each dividing cell, and failure to do so can result in numerous disorders, including birth defects and tumor progression. The Funabiki lab studies how chromosomes signal to spatially and temporally orchestrate rapid assembly and disassembly of macromolecules that ensure accurate chromosome segregation.
Mitosis involves rapid macromolecule assembly and disassembly at the right place, at the right time, and in the right order. Upon entry into mitosis, the nuclear envelope encapsulating the chromosomes disassembles, while a bipolar spindle composed of dynamic microtubule polymers assembles on chromosomes. The kinetochore forms at each chromosomal centromere to capture the microtubule ends, ensuring chromosomal segregation. At the end of segregation, the spindle and the kinetochore disassemble, while the nuclear envelope reforms. The Funabiki lab studies the spatiotemporal mechanisms that control changes to these molecular architectures.
Control of chromosome-induced signals during mitosis. The Funabiki lab has demonstrated that the chromosomal passenger complex (CPC) acts as a master regulator for spatial control of mitosis via the protein kinase Aurora B. Though activated by enrichment on chromosomes, Aurora B helps restrict spindle assembly at chromosomes. Mitosis-specific phosphorylation of histone H3 also plays a part in this process by providing the binding site for CPC. At the end of mitosis, timely dephosphorylation of H3T3ph ensures that the nuclear envelope does not reform before completion of chromosome segregation. Furthermore, Dr. Funabiki’s lab has identified a novel chromatin-associated inhibitor of microtubule polymerization, Dppa2, which helps control the proper size and shape of the nucleus. Through these studies, Dr. Funabiki aims to understand the mechanisms by which chromatin-induced signals orchestrate the order of events during mitosis.
Transduction of microtubule attachment into the chemical signal for chromosome segregation. In order to segregate chromosomes, microtubules must attach to the kinetochore. If not attached, kinetochores activate a signaling pathway called the “spindle assembly checkpoint” to delay sister chromatid separation and exit from mitosis. Dr. Funabiki aims to understand the mechanism by which the microtubule attachment status is recognized and how this physical difference is converted into checkpoint signaling. Furthermore, using super-resolution microscopy, his lab is studying how the three-dimensional architecture of the kinetochore is modulated by microtubule attachment status.
Roles of histone modifications during the cell cycle. Histones are the major protein components of chromosomes and receive a variety of posttranslational modifications. However, due to their critical importance in transcriptional control, it has been difficult to dissect their roles in processes beyond transcription. Recently, the Funabiki lab has established a novel strategy to manipulate histones in egg extracts, which can recapitulate physiological chromosome functions without transcription. Combining this new tool with mass spectrometry, the Funabiki lab examines the role of histones and histone modifications in regulating chromatin and intracellular architecture during the cell cycle.
Kyoto University, 1995–1996
University of California, San Francisco, 1996–2000
Harvard University, 2000–2002
Assistant Professor, 2002–2007
Associate Professor, 2007–2014
The Rockefeller University
Searle Scholar, 2002
Sinsheimer Fund Scholar, 2003
Irma T. Hirschl/Monique Weill-Caulier Trust Research
Zierhut, C. et al. Nucleosomal regulation of chromatin composition and nuclear assembly revealed by histone depletion. Nat. Struct. Mol. Biol. 21, 617–625 (2014).
Ghenoiu, C. et al. Autoinhibition and Polo-dependent multisite phosphorylation restrict activity of the histone H3 kinase Haspin to mitosis. Mol. Cell 52, 734–745 (2013).
Xue, J.Z. et al. Chromatin-bound Xenopus Dppa2 shapes the nucleus by locally inhibiting microtubule assembly. Dev. Cell 27, 47–59 (2013).
Kelly, A.E. et al. Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science 330, 235–239 (2010).
Sampath, S.C. et al. The chromosomal passenger complex is required for chromatin-induced microtubule stabilization and spindle assembly. Cell 118, 187–202 (2004).