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:

  • Wong YYC, Wang Y, Tsui EHL and Yuen KWY^. Argonaute protein CSR-1 restricts localization of holocentromere protein HCP-3, the C. elegans CENP-A homolog. Journal of Cell Science, 2024. 137 (18): jcs261895 https://doi.org/10.1242/jcs.261895
    Pubmed Abstract
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  • Wang Y^, Wong YYC, and Yuen KWY^. Aurora B/AIR-2 is required for sister centromere resolution and centromere protein deposition. Journal of Molecular Cell Biology. 2024. https://doi.org/10.1093/jmcb/mjae045 .
    Pubmed Abstract
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  • Jiang L, Wang X, Zhang D, Yuen KWY^ and Tse YC^. RSU-1 regulates the integrity of dense bodies in muscle cells of aging Caenorhabditis elegans. iScience. 2024. 27(6):109854. https://doi.org/10.1016/j.isci.2024.109854.
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  • 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
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  • 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.
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  • 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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  • 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
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  • 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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  • Jiang Q, Bai J, He M, Yuen KWY and Wong AOL^. Mechanisms underlying the synergistic action of insulin and growth hormone on IGF-I and -II expression in grass carp hepatocytes. Frontiers in Endocrinology. 2018. 9:336. doi.org/10.3389/fendo.2018.00336
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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.
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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
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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.
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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.
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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
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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
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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
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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
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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
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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
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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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Invited Review Articles:
  • Zhu J, Guo Q, Choi M, Liang Z and Yuen KWY^. Centromeric and pericentric transcription and transcripts: their intricate relationships, regulation, and functions. Chromosoma. 2023. 132: 211-230. https://doi.org/10.1007/s00412-023-00801-x
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  • Yuen KWY^, Genomic stability and epigenetic inheritance in holocentric Caenorhabditis elegans and insects (Editorial). Seminars in Cell and Developmental Biology. 2022. https://doi.org/10.1016/j.semcdb.2022.02.021
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  • Wang Y, Wu L and Yuen KWY^. The roles of transcription, chromatin organisation and chromosomal processes in holocentromere establishment and maintenance. Seminars in Cell and Developmental Biology. 2022. https://doi.org/10.1016/j.semcdb.2022.01.004
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  • 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.
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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.
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  • Wong, CYY, Lee, BCH and Yuen KWY^. Epigenetic regulation of centromere function. Cellular and Molecular Life Sciences. 2020, 77, 2899-2917.
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  • Ling YH*, Lin Z and Yuen KWY^. Genetic and epigenetic effects on centromere establishment. Chromosoma. 2020, 129, 1-24.
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  • 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
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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 or Principal Coordinator:

  • Deciphering the Dynamics of Centromeric Protein Assembly and the Mechanism of Sister Centromere Resolution in Caenorhabditis elegans (Principal Investigator, General Research Fund, GRF, 2022-2025, HK$ 1,426,247) (17124922))

  • Systematically Identifying and Determining the Functions of Genes Important for Anoxia-Induced Suspended Animation and Recovery. (Principal Investigator, General Research Fund (GRF), RGC,  2022-2024, HK$1,125,732 (17123621))

  • Determining the Mechanism of Restricting Holocentromere Localization (Principal Investigator, General Research Fund (GRF), RGC, 2021-2023, HK$996,285 (17116520))

  • Elucidating the Mechanism of De Novo Centromere Formation (Principal Coordinator, Collaborative Research Fund (CRF), RGC, 2019-2021, HK$ 5,021,500 (C7058-18G))

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

  • 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 (17126717))
    Abstract

  • The cellular mechanism of anoxia-induced suspended animation C. elegans and S. cerevisiae (Principal Investigator, Young Scientist Fund 2017, The National Science Foundation of China, CNY¥260,000 (31701177))

  • Elucidating the function of the Bre1 E3 ubiquitin ligase in sister chromatid cohesion (Principal Investigator, General Research Grant, RGC, 2015-2017, HK$931,950 (17126714))
    Abstract

  • Deciphering Centromeric Chromatin Assembly Pathway and Dynamics in Holocentric Caenorhabditis elegans (Principal Investigator, General Research Grant, RGC, 2014-2016, HK$866,032 (785313))
    Abstract

  • Determining the Cellular Mechanism of Centromere Establishment (Principal Investigator, Early Career Scheme (ECS), RGC, 2012-2017, HK$3,149,020 (788012M))
    Abstract

Current and Past Lab Members:

Technician:

Abby Mak (ascmak@hku.hk)

Postdoctoral fellows:

2024-Present

Emily Hok Ling Tsui, PhD (HKU)

2023-Present

Jenny Zhenni Zhu, PhD (HKU)

2021-Present

Phyllis Jing Zhu, PhD (HKU)

2019-2024

Charmaine Yan Yu Wong, PhD (HKU)

2023

Eric Yue Wang, PhD (HKU)
• Next Position: Technology Specialist in BioRad

2019-2021

William Zhongyang Lin, PhD (HKU)
• Next Position: Assistant Professor in Shantou University,  China

2018-2019

Hin Ling, PhD (HKU)
• Next Position: Post-doctoral Fellow in Prof. Carl Wu’s Lab, Johns Hopkins University, USA

2017

Wei Zhang, PhD (HKU)
• Next Position: Post-doctoral Fellow in Prof. Pengtao Liu’s Lab, School of Biomedical Sciences, HKU

2016-2017

Sophia So Ngo Lam, PhD (HKU)
• Next Position: Research Associate in Diagnostic Biotechnology Company, HK Science Park

2013-2015

Kyle Ka Lun Law, PhD (McGill)

PhD Students:

2021-Present

Qiao Guo, HKU-Shenzhen Bay Laboratory Joint PhD candidate (co-supervised with Dr. Zhuobin Liang)

2020-2024

Emily Hok Ling Tsui

2019/-2023

Ling Jiang, HKU-South University of Science and Technology Joint PhD candidate (co-supervised with Dr. Yu Chung Tse)

2018-2022

Eric Yue Wang, MSc (HKUST)

2018-2023

Jenny Zhenni Zhu, MSc (HK Polytechnic University)

2015-2020

Phyllis Jing Zhu, MSc (CUHK)
• Selected for Pilot scheme on International Experience for Research Post-graduate Student, Faculty of Science, HKU (2019)
• GRC Carl Storm International Diversity Award, to Gordon Research Conference on Centromere Biology, West Dover, USA (2018)

2013-2018

William Zhongyang Lin

2013-2018

Charmaine Yan Yu Wong
• The 8th Asia Pacific C. elegans Meeting Travel Grant Award, Seoul, South Korea (2018)
• EMBO Travel Bursary, to EMBO Dynamic Kinetochore Workshop, Edinburgh, UK (2017)
• Tigris Educational Fund - Education Scholarship, to Gordon Research Conference on Centromere Biology,
West Dover, VT, USA (2016)

2013-2017

Yick Hin Ling, MPhil (CUHK)
• Selected for Pilot scheme on International Experience for Research Post-graduate Student, Faculty of Science, HKU (2016-2017)

2012-2016

Wei Zhang


MPhil Students:

2020- 2022

Wawa Yuk Wa Lee (co-supervised with Dr. Julie Claycomb)

2016-2020

Jason Ka Ho Mak
• Next position: PhD student in Prof. Andrea Musacchio Lab, Max Planck Institute of Molecular Physiology

2013-2014

Kevin Chi Lok Cheng
• Next position: Research Assistant, Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London

2012-2014

Bernard Chi Hang Lee
• Next position: Croucher PhD student, Department of Pathology, HKU

Teaching and Learning:

Course design and Teaching:

2024-Present

SCNC3111 - Frontiers of science honours seminar course

2024

BIOL3408 – Genetics

2014-2023

BIOL4416 – Stem Cells and Regenerative Biology

2014-Present

BIOL4415 – Healthcare Biotechnology
   

2011-Present

BIOL3401 – Molecular Biology

2013-2023

BIOL1110 – From Molecules to Cells

2016-2022

BIOL3409 – Business Aspects of Biotechnology

2011-2017

BIOL6001 – Postgraduate Seminar Course

Outreach Activities:

Junior Science Institute (for secondary school S4-S6 students): 2013 and 2014 Investigating Genetic Diseases Using Yeast

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

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, transcript, a description of previous research experience and research interests with title [Interest in Yuen lab] to Dr. Karen Yuen.

Last update @ 2025/01/17