Xiangwei He, Ph.D.
Biochemistry and Molecular Biology
Molecular and Human Genetics
- Fudan University, 1988,
- Ph.D., Baylor College of Medicine, 1997
- Postdoctoral Fellow, Massachusetts Institute of Technology, 2001
Chromosome Segregation; Centromere Organization and Kinetochore Assembly
Chromosome segregation is a highly conserved process among eukaryotes. During mitosis spindle microtubules capture chromosomes and pull them apart via a specialized protein complex called kinetochore which is assembled at a specific chromosomal region – the centromere. The mystery of how cells precisely segregate sister chromosome has long fascinated cell biologists and its molecular mechanisms just begin to be unraveled. Understanding how normal cells segregate chromosome precisely is also essential for us to determine which step of the process may go awry in cases of human diseases such as tumors that lead to abnormal chromosome number, which is believed to contribute to tumorigenesis.
Research in my laboratory aims at a specific aspect of chromosome segregation, namely, how each chromosome ensures the assembly of one and only one kinetochore, and how the proper interaction between the spindle microtubules and the kinetochores is established and maintained during mitosis. We reason that the interface between microtubule and kinetochore ought to be the focal point where various mitotic regulatory elements exert their impact on chromosome segregation.
Fission yeast cells undergoing normal mitosis (the left two) and defective mitosis due to a mutation in a kinetochore protein (the right two).
We use the fission yeast Schizosacchromyces pombe as the model organism. The ongoing research covers two areas:
- Kinetochore assembly and function – we previously have contributed to the delineation of the kinetochore architecture through identifying three protein complexes as the structural components and determining their biochemical compositions (EMBO J, 2005), and determining the protein copy numbers of the critical subunits in a kinetochore in vivo (J Cell Biol., 2008). We further demonstrated that the Dam1 complex, which may provide force for chromosome migration, functions as small oligomers, providing key clue to the mechanism for its functions (PNAS, 2010). We wish to further elucidate the specific roles of various other kinetochore components in mediating the interaction between the kinetochore and the spindle.
- Centromeric chromatin organization – we have determined that the centromeric chromatin is comprised of an array of orderly positioned nucleosomes, arguing against the long-term speculation of dynamic nucleosome positioning in centromere (Genome Research, 2008). Contributing to the understanding of the establishment and maintenance of centomere, we found that a key molecule in the pathway, Scm3, associates with the centromere - specific histone H3 (CenpA), but is not an integral part of the nucleosome (Mol. Cell, 2009). We recently have found that CenpA nucleosomes are positioned flexibly within the centromere and that their positioning is inherited epigenetically throughout cell generations (unpublished). We wish to further understand the molecular mechanism underlying the epigenetic inheritance of CenpA positioning.
- Xi Y, Yao J, Chen R, Li W, He X. Nucleosome fragility reveals novel functional states of chromatin and poises genes for activation. Genome Res. 2011 May;21(5):718-24.
- Gao Q, Courtheoux T, Gachet Y, Tournier S, He X. A non-ring-like form of the Dam1 complex modulates microtubule dynamics in fission yeast. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13330-5.
- Pidoux AL, Choi ES, Abbott JK, Liu X, Kagansky A, Castillo AG, Hamilton GL, Richardson W, Rappsilber J, He X, Allshire RC. Fission yeast Scm3: A CENP-A receptor required for integrity of subkinetochore chromatin. Mol Cell. 2009 Feb 13;33(3):299-311.
- Song JS, Liu X, Liu XS, He X. A high-resolution map of nucleosome positioning on a fission yeast centromere. Genome Res. 2008 Jul;18(7):1064-72.
- Joglekar AP, Bouck D, Finley K, Liu X, Wan Y, Berman J, He X, Salmon ED, Bloom KS. Molecular architecture of the kinetochore-microtubule attachment site is conserved between point and regional centromeres. J Cell Biol. 2008 May 19;181(4):587-94.
- Yao J, He X. Kinetochore assembly: building a molecular machine that drives chromosome movement. Mol Biosyst. 2008 Oct;4(10):987-92.
- Liu X, McLeod I, Anderson S, Yates JR 3rd, He X. Molecular analysis of kinetochore architecture in fission yeast. EMBO J. 2005 Aug 17;24(16):2919-30. Epub 2005 Aug 4.
- Rines DR, He X, Sorger PK. Quantitative microscopy of green fluorescent protein-labeled yeast. Methods Enzymol. 2002;351:16-34.
- He X, Rines DR, Espelin CW, Sorger PK. Molecular analysis of kinetochore-microtubule attachment in budding yeast. Cell. 2001 Jul 27;106(2):195-206.
- He X, Asthana S, Sorger PK. Transient sister chromatid separation and elastic deformation of chromosomes during mitosis in budding yeast. Cell. 2000 Jun 23;101(7):763-75.