Professor, Department of Physiology
Professor, Department of Biochemistry and Medical Genetics
Professor, Department of Human Anatomy and Cell Science
Senior Investigator, Research Institute in Oncology and Hematology
Director, The Genomic Centre for Cancer Research and Diagnosis
My epigenetic interests relate to the nuclear organization in cancer and during aging and during the onset and progression of age-related cognitive diseases. There are no published data that link epigenetic modifications to the three-dimensional (3D) order of telomeres and their disruption during the process of carcinogenesis or during age-related cognitive diseases. A comprehensive study on telomere epigenetics using molecular and imaging (including super resolution imaging) approaches may elucidate cancer- and ageing–related changes in the four areas of interest below.
1) Nuclear architecture in cancer
We have developed a quantitative 3D imaging tool to assess the level of genomic instability in cancer cells. Using telomeres, the ends of chromosomes, as indicators for genome (in)stability, we 3D image their nuclear organization and measure it with software we developed [TeloView]. TeloView defines the numbers of telomeres and their sizes, measures the presence of telomeric aggregates, and calculates the overall nuclear position of telomeres, their cell cycle distribution, and the nuclear volume they occupy (1,2). This patented 3D technology has been successfully applied to many cancers, including Hodgkin’s lymphoma (3,4), multiple myeloma (5), myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) (6), chronic myeloid leukemia (7), plasmacytomas (8), and brain tumors (neuroblastoma, ependymoma, glioblastoma, oligodendroglioma) (9 and unpublished data). In all cases, the technology identified patient subgroups whose 3D nuclear telomere profiles were associated with progressive or stable disease. Specifically, we will to investigate whether the change(s) in telomere positions is related to changes in epigenetic marks at the telomeric ends of some or all chromosomes.
2) Nuclear architecture during aging and in aging-related diseases
We have used 3D nuclear telomere profiling of buccal cells to determine nuclear structural changes during onset and progression of Alzheimer’s disease (AD) (10,11) and of mild cognitive impairment (MCI) (11). Using age- and gender-matched controls, we were able to show that the 3D nuclear telomeric organization changes at onset and during progression of AD and is distinct in MCI. Using super resolution imaging, we have further identified changes in DNA organization in both MCI and AD that do not occur in age- and gender-matched controls. Thus, it seems that the nuclear organization is remodeled in aging-related diseases. Although changes in telomeric chromatin have been associated with aging and cellular senescence (12, 13). The contribution of epigenetics to AD and MCI (and other aging-related cognitive diseases) is poorly understood and warrants investigation.
3) ALT cells
Human telomeres are densely enriched by heterochromatin marks such as H3K9me3, H4K20me3, H3K9me2, and H3K79me2. Loss of these heterochromatin marks has been associated with alternative lengthening of telomere (ALT), one of the mechanisms used by cancer cells to maintain their telomeres. ALT cells use recombination for telomere lengthening, and chromatin decondensation, through loss of telomeric heterochromatin marks, is thought to favor this recombination. Exploring loss of telomeric heterochromatin marks at specific telomeric regions and telomeric recombination on the same sites would bring some insight on ALT mechanism.
Our aims are:
1. To study telomere length on each chromosome arm and the rate of sister telomeric exchange in telomerase (used as control) and ALT positive cell lines;
2. From the data generated in aim (1), we will study DNA methylation and heterochromatin marks (H3K9me3, H4K20me3, H3K9me2, and H3K79me2) at some specific subtelomeric regions in ALT and telomerase positive cells.
4) Chromosome movements after oncogene activation
We have demonstrated that MYC deregulation affects chromosome positions transiently (14). As this occurred after telomere aggregates were induced, we hypothesize that chromosome movement may be linked to altered telomere stability in the 3D nuclear space. Current work is investigating the mechanisms of the MYC-induced chromosome movement. We will be exploring the impact of three pathways on MYC oncogene-dependent positional chromosome remodeling; (i) shelterin-dependent changes, (ii) nuclear matrix-mediated changes, and (iii) the analysis of the epigenetic telomere status in presence and absence of MYC deregulation (and before, during and after chromosome movement) using ChIP-seq as described by Vaquero-Sedas et al. 2012 (15).
(1) Vermolen BJ, Garini Y, Mai S, Mougey V, Fest T, Chuang TCY, Chuang AYC, Wark L, and Young IT. Characterizing the Three-Dimensional Organization of Telomeres. Cytometry Part A 67A: 144-150.2005.
(2) Gonzalez-Suarez I, Redwood AB, Vermolen B, Lichtensztejin D, Bhat A, Sullivan T, Sage J, Stewart CL., Mai S and Gonzalo S. Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. Aug 19;28(16):2414-27. 2009. Epub 2009 Jul 23.
(3) Knecht H, Kongruttanachok N, Sawan B, Brossard J, Prevost S, Turcotte E, Lichtensztejn Z, Lichtensztejn D, Mai, S. 3D telomere signatures of Hodgkin- and Reed-Sternberg cells at diagnosis indicate refractory/relapsing Hodgkin’s lymphoma. Translational Oncology. Aug;5(4):269-77. 2012. Epub 2012 Aug 1.
(4) Knecht H, Righolt C, Mai S. Genomic Instability: The Driving Force behind Refractory / Replapsing Hodgkin’s Lymphoma. Cancers 2013, 5(2), 714-725.
(5) Klewes L, Vallente R, Dupas E, Brand C, Grün D, Guffei A, Sathitruangsak C, Awe JA, Kuzyk A, Lichtensztejn D, Tammur P, Ilus T, Tamm A, Rubinger M, Olujohungbe A, Mai S. 3D nuclear telomere organization in multiple myeloma. Translational Oncology 6(6): 749–756. 2013.
(6) Gadji M, Awe JA, Rodrigues P, Kumar R, Houston D, Falcão PR, de Oliveira FM, Mai S. Profiling the Three-Dimensional Nuclear Telomeric Architecture in Myelodysplastic Syndrome and Acute Myeloid Leukemia defines patient subpopulations. Clinical Cancer Research 18(12):3293-304. 2012. Epub 2012 Apr 26. and research highlight.
(7) Samassekou O, Hebert, J, Mai S, Yan J. Nuclear remodeling of telomeres in chronic myeloid leukemia. Genes Chromosomes Cancer 2013. May;52(5):495-502. doi: 10.1002/gcc.22046. Epub 2013 Jan 23.
(8) Kuzyk A and Mai S. Selected telomere length changes and aberrant 3D nuclear telomere organization during fast-onset mouse plasmacytomas. Neoplasia 14(4): 344-351. 2012.
(9) Gadji M, Fortin D, Tsanaclis A-M, Garini Y, Katzir N, Wienburg Y, Yan J, Klewes L, Klonisch T, Drouin R, Mai S. Three-dimensional (3D) nuclear telomere architecture is associated with differential time to progression and overall survival in glioblastoma patients. Neoplasia. 12 (2): 183-191. 2010.
(10) Mathur S, Glogowska A, McAvoy E, Righolt C, Rutherford C, Willing C, Banik U, Ruthirakuban M, Mai S, Garcia A. Three-dimensional quantitative imaging of telomeres in buccal cells identifies mild, moderate and severe Alzheimer patients. J of Alzheimer’s Disease. 2014 Jan 1;39(1):35-48.
(11) Kalaw MC, Klewes L, Righolt C, McAvoy E, Bhullar H, Seo R, Lichtensztejn D, Anderson J, Luedke A, Itorralba J, Mathur S, Rourke D, Katzir N, Garcia A, Mai S. Quantiative 3D telomeric and DNA super resolution imaging of buccal cells non-invasively identify Alzheimer’s disease. 2015 submitted.
(12) McCord RA and Broccoli D. Telomere chromatin: roles in aging, cancer and hereditary disease. Mut Res 2008 Dec1; 647(1-2):86-93.
(13) Decottignies A and d’Adda di Fagagna F. Epigenetic alterations associated with cellular senescence: a barrier against tumorigenesis or a red carpet for cancer? Sem Cancer Biol 2011; Dec; 21 (6):360-6.
(14) Louis SF, Vermolen BJ, Garini Y, Young IT, Guffei A, Zelda Lichtensztejn Z, Kuttler F, Chuang TCY, Moshir S, Mougey V, Chuang, AYC, Kerr PD, Fest T, Boukamp P, Mai S. c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus. Proc Natl Acad Sci (USA) 102(27): 9613-8. 2005.
(15) Vaquero-Sedas MI, Luo C, Vega-Palas MA. Analysis f the epigenetic status of telomeres by using ChIP-seq data. Nucl Acids Res 2012 Nov; 40(21):e163.
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