Research Summary

 

Dr. Lorincz’s laboratory is focused on the interplay between transcription, DNA methylation and histone modifications in early development and in the germline, using the mouse as a model system.
A number of factors have been described that catalyze the post-translational addition or removal of specific moieties, such as acetyl or methyl groups, to/from specific residues on the core nucleosomal histones, features of the so-called “histone code”. Methylation of lysine 4 of the H3 tail, which is associated with the promoter regions of both actively transcribed and “poised” genes, was recently shown to inhibit de novo DNA methylation, thus serving to “protect” promoter regions from DNA methylation. Conversely, we have shown that trimethylation of H3K9 (H3K9me3), a mark associated with transcriptional repression that is inversely correlated with H3K4me3, is enriched in embryonic stem cells at the promoter regions of a subset of germline-specific genes and specific endogenous retroviruses ERVs. This mark is deposited by the H3K9 KMTase Setdb1 (See Matsui et al, Nature, 2010), generally independent of DNA methylation and serves to maintain a number of ERVs in a silent state in cells deficient in all three DNA methyltransferases (See Karimi et al., Cell Stem Cell, 2011). Surprisingly, HP1 proteins, “readers” of the H3K9me3 mark, are dispensable for H3K9me3-mediated proviral silencing (See Maksakova et al, Epigenetics & Chromatin, 2013), raising the question, how does H3K9 methylation inhibit transcription?
Ongoing research in the lab is directed towards characterizing the interplay between readers and writers of covalent histone marks, chromatin remodeling factors and DNA methylation in transcriptional regulation of genes and retroelements (see Thompson et al, PLoS Genetics, 2015 and Sharif et al. Cell Stem Cell, 2016), using knock-down, conventional and CRISPR-based genetic knock-out approaches. Employing Illumina next generation sequencing and bioinformatics pipelines developed in house (see Younesy et al, Bioinformatics, 2014), we systematically characterizing the role of histone H3K9 methyltransferases, H3K9me “readers” and chromatin remodeling factors in ESCs via RNAseq, ChIPseq, meDIPseq and hmeDIPseq analyses (see Liu et al., Genes & Development, 2014).
In complementary genome-wide studies, we are also characterizing the function of LTR elements as alternative genic promoters in ESCs and early embryos as well as germ cells (see Molecular Cell, Thompson et al., 2016) and studying the impact of specific elements on the transcriptome in distantly related mouse strains as well as in rats.
We also recently developed an ultra-low-input micrococcal nuclease-based native ChIP (ULI-NChIP) and sequencing method (See Brind’Amour et al, Nature Communications, 2015) to generate genome-wide histone mark profiles with high resolution from as few as 103cells. We demonstrate that ULI-NChIP-seq generates high-quality maps of covalent histone marks from 103 to 106 embryonic stem cells. Subsequently, we showed that ULI-NChIP-seq H3K27me3 profiles generated from E13.5 primordial germ cells isolated from single male and female embryos show high similarity to recent data sets generated using 50–180x more material. We are currently applying this method to address fundamental questions about intergenerational inheritance of covalent histone marks and their role in enhancer function and the inheritance of DNA methylation in the early mouse embryo.

 

Technologies & Methods
Teaching

Principal Supervisor, Julien Richard Alberts, Doctorate
Start Date: 2013/9
Role of KRAB-ZFPs expressed in early mouse development in silencing of endogenous retroviruses

Principal Supervisor, Julie Brind’Amour, Post-doctorate
Start Date: 2012/2
Epigenetic basis of ERV silencing in the germ line and early mouse development

Principal Supervisor, Chialu Chen, Doctorate
Start Date: 2011/8
Interplay between H3S10 phosphorylation and H3K9 methylation in transcriptional regulation

Principal Supervisor, Peter Thompson, Doctorate
Start Date: 2010/7
Role of the chromatin remodeler Smarca5 in transcriptional regulation in ES cells

Principal Supervisor, Mehdi Karimi,
Start Date: 2010/5
Bioinformatic analysis of genome-wide chip-seq and RNAseq data in ES cells

Principal Supervisor, Sarah Lepage, Master’s Thesis
Start Date: 2009/9

Principal Supervisor, Sheng Liu, Doctorate
Start Date: 2014/12
Analysis of the role of SETDB1 in regulation of piRNA biogenesis genes in the germline

Principal Supervisor, Irina Maksakova, Post-doctorate
Start Date: 2008/10
Genome-wide identification and analysis of epigenetic repressors of tumour suppressor genes

Principal Supervisor, Danny Leung, Doctorate
Start Date: 2007/9

Principal Supervisor, Margaret Rush, Post-doctorate
Start Date: 2006/4
A novel genomic targetting approach to identify therapuetic agents for treating Fragile X Syndrome

Principal Supervisor, Kevin Dong, Master’s Thesis
Start Date: 2005/9

Awards

Distinguished Achievement Award, Excellence in Basic Science Research, UBC 2014

Publications

 
Comprehensive List
Google Scholar

Selected Publications

  1. Peter J. Thompson, Vered Dulberg, Kyung-Mee Moon, Leonard J. Foster, Carol Chen, Mohammad M. Karimiand Matthew C. Lorincz hnRNP K coordinates transcriptional silencing by SETDB1 in embryonic stem cells. In Press, PLoS Genetics (Dec, 2014)
  2. Julie Brind’Amour, Matthew Hudson, Sheng Liu, Carol Chen, Mohammad M Karimi and Matthew C Lorincz Ultra-low-input native ChIP-seq for genome-wide profiling of rare cell populations.In Press, Nature Communications, (Dec, 2014)
  3. Jichang Wang, Gangcai Xie, Avazeh T. Ghanbarian, Manvedra Singh, Attila Szvetnik, Wei Chen, Matthew C. Lorincz, Zoltan Ivics, Laurence D. Hurst, Zsuzsanna Izsvák. Primate-specific endogenous retrovirus driven transcription defines naïve-like stem cells. Nature 516, 405-409, 17 Dec (2014)
  4. Sheng Liu, Julie Brind’Amour, Mohammad Mehdi Karimi, Kenjiro Shirane, Aaron Bogutz, Louis Lefebvre, Hiroyuki Sasaki, Yoichi Shinkai, Matthew C Lorincz. Setdb1 is required for persistence of H3K9me3 and repression of endogenous retroviruses in mouse primordial germ cells. Genes & Development 28:2041–2055 Sept (2014)
  5. Danny Leung, Tingting Du, Ulrich Wagner, Wei Xie, Ah Young Lee, Preeti Goyal, Yujing Li, Keith E. Szulwach, Peng Jin, Matthew C. Lorincz, and Bing Ren. Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1. Proc Natl Acad Sci USA. 22 Apr (2014)
  6. Hamid Younesy, Torsten Moller, Alireza Heravi-Moussavi, Jeffrey B. Cheng, Joseph F. Costello, Matthew C. Lorincz, Mohammad M. Karimi,and Steven J.M. Jones. ALEA: a toolbox for allele-specific epigenomics analysis. Bioinformatics. 21 Jan (2014)
  7. Kathryn Blaschke, Kevin T. Kabata, Mohammad M. Karimi, Jorge A. Zepeda-Martinez, Preeti Goyal, Sahasransu Mahaptra, Angela Tam, Diana J. Laird, Martin Hirst, Anjana Rao, Matthew C. Lorincz, and Miguel Ramalho-Santos. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature, 500, 222-226. 8 August (2013)
  8. H. Younesy, C.B. Nielsen, T. Moller, O. Alder, R. Cullum, M.C. Lorincz, M.M. Karimi, and S.J.M. Jones. An Interactive Analysis and Exploration Tool for Epigenomic Data. Computer Graphics Forum (Proceedings of EuroVis 2013), 32(3), (2013)
  9. Sylvie Rival-Gervier, Mandy Y.M. Lo, Shahryar Khattak, Peter Pasceri, Matthew C. Lorincz, and James Ellis. Kinetics and Epigenetics of Retroviral Silencing in Mouse Embryonic Stem Cells Defined by Deletion of the D4Z4 Element. Mol Ther Aug; 21(8):1536-50. doi: 10.1038/mt.2013.131 (2013)
  10. Irina A. Maksakova, Peter J. Thompson, Preeti Goyal, Steven J.M. Jones, Prim B. Singh, Mohammad M. Karimi, and Lorincz C. Matthew. Distinct roles of KAP1, HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells. Epigenetics & Chromatin Jun 4;6(1):15 (2013)
  11. Maltby V, Martin B, Brind’Amour J, Chruscicki A, McBurney K, Schulze J, Johnson I, Hills M, Hentrich T, Kobor M, Lorincz M, Howe, L. Histone H3K4 demethylation is negatively regulated by histone H3 acetylation in Saccharomyces cerevisiae. PNAS, USA 109:45 18505-18510, (2012)
  12. Danny C. Leung and Matthew C. Lorincz. Silencing of endogenous retroviruses: when and why do histone marks predominate? Trends in Biochemical Sciences (Cover article) 37:4, 127-133 (2012)
  13. Rita Rebollo, Mohammad M. Karimi, Misha Bilenky, Liane Gagnier, Katharine Miceli-Royer, Ying Zhang, Preeti Goyal, Thomas M. Keane, Steven Jones, Martin Hirst, Matthew C. Lorincz* and Dixie L. Mager* (*corresponding authors). Retrotransposon-induced heterochromatin spreading in the mouse revealed by insertional polymorphisms PLoS Genetics 7(9): e1002301 (2011)
  14. Irina A. Maksakova, Preeti Goyal, Jörn Bullwinke, Jeremy P. Brown, Misha Bilenky, Dixie L. Mager, Prim B. Singh and Matthew C. Lorincz. H3K9me3 binding proteins are dispensable for SETDB1/H3K9me3-dependent retroviral silencing. Epigenetics & Chromatin, 4:12 doi:10.1186/1756-8935-4-12 (2011)
  15. Karimi, M. M., P. Goyal, I. A. Maksakova, M. Bilenky, D. Leung, J. X. Tang, Y. Shinkai, D. L. Mager, S. Jones, M. Hirst, and M. C. Lorincz. DNA Methylation and SETDB1/H3K9me3 Regulate Predominantly Distinct Sets of Genes, Retroelements, and Chimeric Transcripts in mESCs. Cell Stem Cell 8:676-87 (2011)
  16. Leung, D. C., K. B. Dong, I. A. Maksakova, P. Goyal, R. Appanah, S. Lee, M. Tachibana, Y. Shinkai, B. Lehnertz, D. L. Mager, F. Rossi, and M. C. Lorincz. Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment, but not the maintenance, of proviral silencing. PNAS, USA 108:5718-23 (2011)
  17. Toshiyuki Matsui, Danny Leung, Hiroki Miyashita, Hitoshi Miyachi, Hiroshi Kimura, Makoto Tachibana, Matthew C. Lorincz* and Yoichi Shinkai* (*corresponding authors). Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature, 464, 927-931 8 April (2010)
  18. Margaret Rush, Ruth Appanah, Sandra Lee, Lucia L. Lam, Preeti Goyal, Matthew C. Lorincz. Targeting of EZH2 to a defined genomic site is sufficient for recruitment of DNMT3a but not de novo DNA methylation. Epigenetics, 4:6 1-11 (2009)
  19. Michael S. Kobor and Matthew C. Lorincz. H2A.Z and DNA methylation: a mutually exclusive relationship. Trends in Biochemical Science. 34:158-61 (2009)
  20. Kevin B. Dong, Irina A. Maksakova, Fabio Mohn, Danny Leung, Ruth Appanah, Sandra Lee, Hao W. Yang, Lucia L. Lam, Dixie L. Mager, Dirk Schübeler, Makoto Tachibana, Yoichi Shinkai and Matthew C. Lorincz. DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity. EMBO J., 27:2691-701 (2008)
  21. M. C. Lorincz and D. Schübeler. RNA polymerase II: Just Stopping By. Cell, 130: 16-18 (2007)
  22. Appanah, R., D. R. Dickerson, P. Goyal, M. Groudine and M. C. Lorincz.
    An Unmethylated 3′ Unmethylated 3′ Promoter-Proximal Region Is Required for Efficient Transcription Initiation. PLoS Genetics. 3.2: e27 doi:10.1371/journal.pgen.0030027 (2007)
  23. Laura B. Sontag, M. C. Lorincz and E. Georg Luebeck. Dynamics, stability and inheritance of somatic DNA methylation imprints. Journal of Theoretical Biology, 242:4, 890-899 (2006)
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