Hironori Funabiki, Ph.D.
The core operating program for life forms is encoded in chromosomes, which are composed of genomic DNA and chromatin proteins. During mitosis, a full set of chromosomes must be equally transmitted to the offspring of each dividing cell. Failures in this process can result in numerous disorders, such as cancers. Funabiki studies the molecular signatures and mechanisms of accurate mitosis, and the consequences of mitotic failures.
Every person has trillions of cells that are produced and maintained by massive numbers of cell divisions. Human cells typically have 46 chromosomes, but this number often deviates in cancer cells. Cellular DNA content can be also altered by invasion of pathogenic DNA. The Funabiki lab studies the mechanisms by which cells ensure accurate chromosome numbers, detect abnormal chromosomes and foreign DNA, and adapt to these aberrations or eliminate them. Through this work, the Funabiki lab aims to understand the molecular basis for cancers and other diseases.
The structural and signaling roles of the nucleosome during mitosis. For successful cell divisions, meter-long strands of genomic DNA must be compacted 10,000-fold into mitotic chromosomes with distinct shapes and sizes. Mitotic chromosomes also promote assembly of functional architectures, such as spindles and kinetochores, which mediate chromosome segregation. The primary folding unit of genomic DNA is the nucleosome, which is comprised of 150 base pairs of DNA wrapped around histone proteins. The Funabiki lab studies how this nanometer-scale nucleosome shapes the structure and function of mitotic chromosomes. The lab developed a strategy to reconstitute the nucleosome using recombinant histones in the physiological cell-free system, which allowed them to reveal the mechanism by which nucleosomes drive the assembly of machineries that control mitosis. The Funabiki lab now combines proteomics, innovative imaging techniques, and cryo-electron microscopy to define how architectural and functional organizations of chromosomes are regulated to control mitosis.
Centromere integrity. Specialized chromosome segments called centromeres control chromosome segregation. They are composed of long arrays of repetitive sequences, called satellite DNAs. Why and how centromeres maintain this repeat organization remains enigmatic. The Funabiki lab revealed that the repeats become relatively unstable in human cancer cell lines, and unveiled the role of a centromere-specific histone variant in the repeat stability. The lab also characterized a novel nucleosome remodeling complex that is mutated in a rare condition called immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, which is associated with DNA methylation at centromere-associated satellite DNAs. In characterizing the key mechanism that helps maintain the repeat sequences, Funabiki aims to unveil the functional consequence of centromere instability and its relevance to disease.
Chromosome identity, mitotic failures, and cancers. To defend against foreign DNA, a cellular sensor called cGAS recognizes cytoplasmic DNA and induces inflammation. The Funabiki lab found that host DNA does not have this effect because its nucleosomes act as a chromosomal signature that prevents cGAS activation. However, aberrant mitosis, which is induced by cancer chemotherapies, leads to cGAS-dependent cell death. Funabiki studies the mechanism behind the nucleosome-dependent cGAS suppression, and the role of cGAS signaling during cancer chemotherapies.