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:

  • Lin Z, Xie Y, Nong W, Ren X, Li R, Zhao Z, Hui JH and Yuen KWY^. Formation of artificial chromosomes in Caenorhabditis elegans and analyses of their segregation in mitosis, DNA sequence composition and holocentromere organization. Nucleic Acids Research. 2021, https://doi.org/10.1093/nar/gkab690.
    Pubmed Abstract
    Full Text

  • Lin Z and Yuen KWY^. RbAp46/48LIN-53 and HAT-1 are required for initial CENP-AHCP-3 deposition and de novo centromere formation in Caenorhabditis elegans embryos. Nucleic Acids Research. 2021. https://doi.org/10.1093/nar/gkab217.
    Pubmed Abstract
    Full Text

  • Lin Z and Yuen KWY^. Construction and analysis of worm artificial chromosomes with de novo holocentromeres in Caenorhabditis elegans. Essays in Biochemistry. 2020, 64 (2): 233–249.
    Pubmed Abstract

  • Ling YH*, Lin Z and Yuen KWY^. Genetic and epigenetic effects on centromere establishment. Chromosoma. 2020, 129, 1-24.
    Pubmed Abstract

  • Iannucci A, Cannicci S^, Lin Z, Yuen KWY, Ciofi C, Stanyon R and Fratini S. Cytogenetic of Decapoda Brachyura: testing technical aspects for obtaining metaphase chromosomes in six mangrove crab species. Caryologia. 2020, 73(2):39-49.
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  • Wong, CYY, Ling, YH., Mak, JKH, Zhu, J and Yuen KWY^. Lessons from the extremes: Epigenetic and genetic regulation in point monocentromere and holocentromere establishment on artificial chromosomes. Experimental cell research. 2020, 390, 111974.
    Pubmed Abstract

  • Wong, CYY, Lee, BCH and Yuen KWY^. Epigenetic regulation of centromere function. Cellular and Molecular Life Sciences. 2020, 77, 2899-2917.
    Pubmed Abstract

  • Bao X, Liu Z, Zhang W, Gladysz K, Fung YME, Tian G, Xiong Y, Wong JWH, Yuen KWY^ and Li XD^. Glutarylation of Histone H4 Lysine 91 Regulates Chromatin Dynamics. Molecular Cell. 2019 Nov 21;76(4):660-675.e9.
    Pubmed Abstract

  • Ling YH and Yuen KWY^. Point centromere activity requires an optimal level of centromeric non-coding RNA. Proceedings of the National Academy of Sciences. 2019. doi.org/10.1073/pnas.1821384116
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  • Zhu J*, Cheng K* and Yuen KWY^. Histone acetylation Facilitates Centromere Establishment on Artificial Chromosomes in Caenorhabditis elegans. Epigenetics and Chromatin. 2018. 16:11. doi.org/10.1186/s13072-018-0185-1
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  • Zhang W, Yeung CHL, Wu L and Yuen KWY^. Bre1 is Required for Sister Chromatid Cohesion Establishment in Saccharomyces cerevisiae. eLife. 2017. 6. pii: e28231. doi: 10.7554/eLife.28231.
    Pubmed Abstract
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  • Fung RSK, Jin B, He M, Yuen KWY and Wong AOL^. Grass Carp Follisatin: Molecular cloning, Functional characterization, Dopamine D1 regulation at Pituitary level, and implication in growth hormone regulation. Frontiers in Endocrinology. 2017. doi: 10.3389/fendo.2017.00211
    Pubmed Abstract
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  • Fung RSK, Bai J, Yuen KWY, Wong AOL^. Activin/follistatin system in grass carp pituitary cells: - Regulation by local release of growth hormone and luteinizing hormone and its functional role in growth hormone synthesis and secretion. PLoS One. 2017. doi: 10.1371/journal.pone.0179789.
    Pubmed Abstract
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  • 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. 2016. 177:454-463.
    Pubmed Abstract
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  • Lee B.C.H., Lin Z and Yuen K.W.Y.^. RbAp46/48LIN-53 is Required for Holocentromere Assembly in Caenorhabditis elegans. Cell Reports. 2016. 14:1819-1828. doi: 10.1016/j.celrep.2016.01.065
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    Cell Reports Facebook Highlight

  • 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
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  • 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
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    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
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  • 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
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  • 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
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  • 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
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  • 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
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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
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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:

As Principal Investigator:

  • Elucidating the Mechanism of De Novo Centromere Formation (Principal Investigator, Collaborative Research Fund, CRF, 2019-2021, HK$ 5,021,500)

  • Epigenetic Regulation of Point Centromeres by Centromeric Non-coding RNA Transcription (Principal Investigator, General Research Grant, RGC, 2019-2021, HK$ 972,000 Abstract

  • 秀丽隐杆线虫和芽殖酵母中乏氧诱至的假死状态之细胞机制研究.国家自然科学基金,青年科学基金项目, CNY26.00万元. The cellular mechanism of anoxia-induced suspended animation C.elegans and S. cerevisiae (Principal Investigator, Young Scientist Fund, The National Science Foundation of China)

  • Holocentric but not everywhere on the chromosome: How and where does histone chaperone RbAp46/48/LIN-53 assemble Centromeric Protein A (CENP-A/HCP-3) in Caenorhabditis elegans? (Principal Investigator, General Research Grant, RGC, 2018-2020, HK$1,221,692)
    Abstract

  • 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

As Co-Investigator:

  • High-resolution Live-cell Imaging System for Quantifying Long-term 3D Dynamics of Large Tissue Models and Organisms, (as Co-I) (PI: Dr. Jade Shi), Collaborative Research Fund (CRF) - Major Equipment Project, 2017/2018 (Duration: 3 years), RGC, HK$ 3,466,130

  • 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@hku.hk))

Postdoctoral fellow:

  • Hin Ling, 2017-
  • William Lin, 2019-
  • Charmaine Wong 2019-
Postgraduates:
  • Jason Ka Ho Mak, 2016-
  • Phyllis Zhu, 2015-
  • Eric Wang, 2018-
  • Jenny Zhu, 2018-
Undergraduates:
  • Jasmine Chit Ying Lau, Student Volunteer, 2018-

Alumni:

Post-graduates & Post-docs: 

  • Wei Zhang, PhD Student, 2012-2016; Postdoctoral Fellow, 2016-2018
  • Sophia Lam, Postdoctoral Fellow, 2017-2018
  • Kevin Cheng, MPhil Student, 2013-2015; Currently: Research Assistant, the Centre for Genomics & Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
  • Bernard Lee, Final Year Project Student, 2011-2012; MPhil Student, 2012-2014; Currently: Research Assistant at Department of Pathology, HKU
  • Kyle Law, Postdoctoral Fellow, 2013-2015 

Undergraduates: 

  • Keith Yip, Summer Research Fellowship Student, 2018
  • Judith Junran Yan, University Research Fellowship Student, Final Year Project Student, 2017-2018
  • Crystal Tang, Final Year Project Student, 2017-2018
  • Winsum Wing Sum Chan, Final Year Project Student, 2017-2018
  • Clarissa Linardi, Part-time Research Assistant, 2017-2018
  • Raissa Regina Ng, Internship Student, 2018, Summer Research Fellowship Student, 2017
  • Joe Kai Ching Lam, Summer Research Fellowship Student, 2017
  • Katie Chin Ching Tsoi (Imperial College London), Summer Volunteer, 2017
  • Gami Lok Yee Hiok, Part-time Research Assistant, 2016-2017
  • Scarlet Tsz Hing Cho, Directed Study Student, 2016-2017
  • Marvin Yu Cheng, Directed Study Student, 2016-2017
  • Trupti Naik, Summer Internship Student, 2016
  • Monique Lai, Part-time Research Assistant, 2014-2015; Currently: Research assistant, School of Nursing, Polytechnic University
  • Amy Wu, Summer Research Fellowship Student, 2013; Final Year Project Student, 2014-2015; Currently: MSc student, Columbia University Mailman School of Public Health
  • Clarence Yeung (University of British Columbia), Summer Student Research Assistant, 2014
  • Rachel Chan (McGill University), Summer Student Research Assistant
  • Ken Cho, Undergraduate Volunteer, 2013-2014; Currently: Research Assistant, Department of Computing Science, HKU
  • 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; Currently PhD student at the Genome Science and Technology (GSAT) program, University of British Columbia, Canada

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 @ 2018/04/20