Research Interests:

Every cell must replicate and segregate their genome faithfully during each cell cycle. Errors in chromosome segregation during mitosis or meiosis can result in chromosome gain or loss (aneuploidy) and chromosome instability (CIN), which may lead to cancer progression, spontaneous abortion or birth defects, such as Down syndrome. Understanding the cellular mechanisms that ensure accurate chromosome segregation is fundamentally important and medically relevant. The underlying mechanism can also be applied to the development of artificial chromosome technology for gene therapy purpose.

 

Centromere Establishment and Propagation

Centromere is the specialized chromatin domain for directing chromosome segregation. At entry into mitosis, a multi-protein complex, called the kinetochore, assembles on the centromere of each sister chromatid to mediate attachment to the mitotic spindle for chromosome movement. Centromeric DNA sequences and sizes vary dramatically among eukaryotes, from 125b in the budding yeast S. cerevisiae to megabases of satellite repeats in vertebrates, and to a diffuse centromere (holocentromere) along the length of the chromosome in the nematode C. elegans, some insects and plants. Yet, kinetochore proteins and architecture are highly conserved. Importantly, all active centromeres contain a histone H3 variant, CENP-A / CenH3, which replaces H3 in centromeric nucleosomes. CENP-A is proposed to serve as an epigenetic mark for centromere identity, in addition to acting as a foundation for assembly of the kinetochore. Occasionally, neocentromeres can form on non-centromeric DNA sequence, and introduction of naked centromeric sequences into cells can form stably propagating artificial chromosomes at very low frequencies. However, how the CENP-A centromeric domain is first established and how it is maintained through generations and mitotic cell cycles is not well understood.

Fig 1 C. elegans, a soil nematode. ~1mm in length

Fig 2 DNA Kinetochore Microtubules. A 1-cell embryo in anaphase of mitosis

Fig 3 Extra-chromosomal array forms de novo centromere and autonomously segregation in mitosisUsing C. elegans as a model, we combine molecular biology, genetics, live cell imaging, biochemistry, genomics and proteomics to study the mechanisms of centromere establishment and propagation. We found that in C. elegans, injection of naked DNA devoid of any C. elegans genomic sequence can result in formation of autonomously segregating extra-chromosomal arrays containing de novo centromeres at high frequencies. Understanding what factors determine centromere formation will advance the engineering of artificial chromosomes for stable delivery of therapeutic genetic information.


Chromosome Instability (CIN) in Cancers

Chromosome instability (CIN) and aneuploidy are hallmarks of many solid cancers, and CIN has been proposed to drive tumor progression and heterogeneity. An increased rate of chromosome missegregation has been suggested as a cause of CIN. Overexpression of CENP-A and other kinetochore proteins have also been observed in cancer cells, causing ectopic kinetochore formation and chromosome missegregation.

To systematically determine the genetic basis of CIN, we have developed chromosome stability assays in model organisms. Most basic cellular mechanisms, such as cell cycle regulation and chromosome segregation, and the genes functioning in these pathways are well conserved throughout eukaryotes. The budding/brewer yeast S. cerevisiae is a single-cell eukaryotic organism with ~6,600 genes. Using a systems biology and functional genomics approach in the budding yeast, we can identify and characterize genes important for maintaining genome integrity, including genes involved in kinetochore function, sister chromatid cohesion, mitotic spindle assembly, DNA repair, DNA replication, chromatin assembly, etc. Understanding the genetic and phenotypic differences between CIN tumor cells and normal cells will facilitate the development of cancer therapies that specifically selects against CIN cells. Taking advantage of the ease in genetic manipulation and the rapid, robust cell cycle in yeast, we can also develop assays to screen for CIN cell-selective drugs.

Fig 4 Budding yeast S. cerevisiae

Fig 5 Yeast Gene Deletion Library

Fig 6 Red-white sectoring yeast colonies, indicative of freguenty chromosome loss


Publications:

(* These authors contributed equally to the work)
(^ Corresponding author)

Research articles:

  • Lai K, Li J, Chan C, Chan T, Yuen K, Chiu J. Transcriptiomic alterations in Daphnia magna embryos from mothers exposed to hypoxia. Aquatic Toxicology. 177:454-463.
    Pubmed Abstract
    Full Text
  • Han X.B., Yuen K.W.Y. and Wu S.S. Polybrominated diphenyl ethers affect the reproduction and development, and alter the sex ratio of zebrafish (Danio rerio). Environmental Pollution. 2013. 182:120-6. doi: 10.1016/j.envpol.2013.06.045
    Pubmed Abstract
    Full Text
  • Gassmann R*, Rechtsteiner A*, Yuen K*, Muroyama A, Monen J, Barron F, Maddox P, Monen J, Egelhofer T, Ercan S, Oegema K, Lieb J, Strome S, and Desai A. An Inverse Relationship to Germline Transcription Defines the C. elegans Holocentromere in Progeny. Nature. 2012. 484(7395):534-7. doi:10.1038/nature10973
    Pubmed Abstract
    Full Text
    F1000 Prime Article Recommendation
  • Yuen K, Nabesima K, Oegema K, and Desai A. Rapid De Novo Centromere Formation Occurs Independently of Heterochromatin Protein 1 in C. elegans Embryos. Current Biology. 2011. 21(21):1800-7. doi: 10.1016/j.cub.2011.09.016
    Pubmed Abstract
    Full Text
  • Ben-Aryoa S, Agmon N, Yuen K, Kwok T, McManus K, Kupiec M, and Hieter P. Proteasome Nuclear Activity Affects Chromosome Stability by Controlling the Turnover of DNA Repair Proteins. PLoS Genetics. 2010. 6(2):e1000852. doi: 10.1371/journal.pgen.1000852
    Pubmed Abstract
    Full Text
  • Barber T*, McManus K*, Yuen K*, Reis M, Parmigiani G, Shen D, Barrett I, Nouhi Y, Spencer F, Markowitz S, Velculescu V, Kinzler K, Vogelstein B, Lengauer C, and Hieter P. Chromatid Cohesion Defects may Underlie Chromosome Instability in Human Colorectal Cancers. Proc Natl Acad Sci U S A. 2008. 105(9):3443-8. doi: 10.1073/pnas.0712384105
    Pubmed Abstract
    Full Text
  • Yuen K*, Warren C*, Chen O, Kwok T, Hieter P, and Spencer F. Systematic Genome Instability Screens in Yeast and their Potential Relevance to Cancer. Proc Natl Acad Sci U S A. 2007. 104(10):3925-3930. doi: 10.1073/pnas.0610642104
    Pubmed Abstract
    Full Text
  • Measday V*, Baetz K*, Guzzo J, Yuen K, Kwok T, Sheikh B, Ding H, Ueta R, Hoac T, Cheng B, Pot I, Tong A, Yamaguchi-Iwai Y, Boone C, Hieter P, and Andrews B. Systematic Yeast Synthetic Lethal and Synthetic Dosage Lethal Screens Identify Genes Required for Chromosome Segregation. Proc Natl Acad Sci U S A. 2005. 102(39):13956-61. doi: 10.1073/pnas.0503504102
    Pubmed Abstract
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Reviews:

  • Yuen K. Chromosome Instability (CIN), Aneuploidy and Cancer. Encyclopedia of Life Sciences. 2010.  doi: 10.1002/9780470015902.a0022413.
    Abstract

  • Yuen K, and Desai A. The Wages of CIN. Journal of Cell Biology. 2008. 180(4):661-3. doi: 10.1083/jcb.200801030
    Pubmed Abstract
    Full Text

  • Yuen K*, Montpetit B*, and Hieter P. The kinetochore and cancer: what's the connection? Current Opinion in Cell Biology. 2005. 17(6):576-82. doi:10.1016/j.ceb.2005.09.012
    Pubmed Abstract
    Full Text

In preparation:

  1. Cheng K., Zhu J., Lin Z. and Yuen K.W.Y.^. Histone acetylation is Important for Centromere Establishment on Artificial Chromosomes in Caenorhabditis elegans.
  2. Zhang W. and Yuen K.W.Y.^. Bre1 is Required for Sister Chromatid Cohesion Establishment in Saccharomyces cerevisiae
  3. Bao X, Zhang W, Yuen K.W.Y.^ and Li XD^. Glutarylation at histone H4 lysine 91 regulates nucleosome assembly.
  4. Wong C, Law Kand Yuen K.W.Y.^. Ego-1 and Csr-1 RNA Interference Pathway Restricts Holocentromeric Localization of CENP-A/Hcp-3 in Caenorhabditis elegans.
  5. Ling H.L and Yuen K.W.Y.^. Centromeric Long Non-coding RNA Is Required for Centroemere Function in Saccharomyces cerevisiae.

Selected Awards:

  • 2016 Second Prize for the Best Research Output, Strategic Research Theme – Development and Reproduction, HKU (for Cell Reports. 2016. 14:1819-1828)

  • 2012 Early Career Award, Research Grant Council (RGC) of Hong Kong

  • Hong Kong Croucher Foundation Post-Doctoral Fellowship (tenured at Dr. Arshad Desai Lab, Ludwig Institute for Cancer Research / Department of Cellular & Molecular Medicine, University of California, San Diego, USA)

  • National Sciences and Engineering Research Council of Canada (NSERC) Postgraduate Scholarships A & B (tenured at Dr. Phil Hieter Lab, Department of Medical Genetics / Michael Smith Laboratories, University of British Columbia, Canada)

  • Simon Fraser University Chemistry / Biochemistry Award


External Research Grants:

  • Elucidating the function of the Bre1 E3 ubiquitin ligase in sister chromatid cohesion (Principal Investigator, General Research Grant, RGC, 2015-2017, HK$931,950)
    Abstract

  • Deciphering Centromeric Chromatin Assembly Pathway and Dynamics in Holocentric Caenorhabditis elegans (Principal Investigator, General Research Grant, RGC, 2014-2016, HK$866,032)
    Abstract

  • Determining the Cellular Mechanism of Centromere Establishment (Principal Investigator, Early Career Scheme (ECS), RGC, 2012-2017, HK$3,149,020)
    Abstract

  • Establishment of a shared live cell imaging platform for super-resolution microscopy, (as Co-I) (PI: Prof. George Tsao), Collaborative Research Fund (CRF) - Major Equipment Project, 2015/2016 (Duration: 3 years), RGC, HK$ 4,000,000

Awards by Students:

2016/07 Charmaine Wong, PhD student
Tigris Educational Fund - Education Scholarship 2016
HK$10,000.00 for travel to Gordon Conference on Centromere Biology. West Dover, VT, USA
2012/06-08 Anjana Kulasekara, Summer Research Fellowship Student
Obtained Excellence in Poster Presentation in the Faculty of Science, HKU

Current Team:

Technician:
  • Abby Mak (ascmak at hku.hk)

Postdoctoral fellow:

  • Sophoia Lam, 2016-
Postgraduates:
  • Jason Ka Ho Mak, 2016-
  • Phyllis Zhu, 2015-
  • Hin Ling, 2013-
  • Charmaine Wong, 2013-
  • William Lin, 2012-
  • Wei Zhang, 2012-2016
Undergraduates:
  • Gami Lok Yee Hiok, Work-Study Student (Part-time Research Assistant)
  • Scarlet Tsz Hing Cho, Directed Study Student
  • Marvin Yu Cheng, Directed Study Student

Alumni:

  • Trupti Shivaprasad Naik, Summer Internship Student , 2016
  • Monique Sin Yi Lai, Part-time Research Assistant, 2014-2015
  • Kevin Cheng, MPhil Student, 2013-2015
  • Clarence Hue Lok Yeung (University of British Columbia), Summer Student Research Assistant, 2014
  • Rachel Tin Sum Chan (McGill University), Summer Student Research Assistant, 2014
  • Bernard Lee, Final Year Project Student, 2011-2012; MPhil Student, 2012-2014, Research Assistant, 2014
  • Kyle Law, PDF, 2013-2015
  • Amy Liwen Wu, Summer Research Fellowship Student, 2013; Final Year Project Student, 2014-2015
  • Ken Ling Cho, Undergraduate Volunteer, 2013-2014
  • Yorky Wong, Final Year Project Student, 2012-2013
  • Leo Lao, Summer Internship Student, 2012
  • Disha Parikh, Summer Helper, 2012; Directed Study Student, 2012-2013
  • Anjana Kulasekara, Summer Research Fellowship Student, 2012
  • Horace Chan, Directed Study Student, 2011-2012
  • Frank Ye, Undergraduate Volunteer, 2011-2012

Research Opportunities:

We are seeking enthusiastic and motivated members to join our team as:

Experience in molecular biology, microscopy, cell biology, and genetic analysis would be an asset. Interested applicants should send your CV with a description of previous research experience and research interests to Dr. Karen Yuen.


Teaching and Outreach Activities:

Undergraduate courses:
BIOL1110 From Molecules to Cells
BIOL 2303/3401 Molecular Biology (Course Coordinator)
BIOL 3315/4415 Healthcare Biotechnology
BIOL3326/4416 Stem Cells and Regenerative Biology (Course Coordinator)

Postgraduate courses:
BIOL 6001 Presentation skills and research seminars in Biological Sciences (Molecular Biology and Biotechnology Module Coordinator)

Junior Science Institute (for secondary school S4-S6 students):
Investigating Genetic Diseases Using Yeast
2014/07/15
2013/07/16
2013/03/19

HK Science Museum Talk:
2013/12/14 2013 Nobel Prize in Medicine

Graduate Study Workshop:
2012/11/08 How to Prepare for your Research Postgraduate Study? When and Where?

Internship Training:
2012 Summer Workshop for Secondary School Teachers at Caritas Chan Chun Ha Field Studies Centre, Cheung Chau


Last update @ 2017/07/13