Scientist Level 2, CFRI
Senior Scientist, Centre for Molecular Medicine and Therapeutics at CFRI
Professor, Department of Medical Genetics, University of British Columbia
Tier 1 Canada Research Chair in Social Epigenetics

Phone: 604-875-3803

Assistant: Tanya Erb

Assistant Phone: 604-875-2345 ext. 5901

Mailing Address: Room 2008, 950 West 28th Avenue, Vancouver BC V5Z 4H4

Overview

As the sole carrier of genetic information, DNA does not exist as a naked template in the eukaryotic genome; instead DNA exists as a chromatin structure amenable to the changing environment, especially during the sensitive period of childhood. Not surprisingly, many complex regulatory mechanisms act on chromatin to ensure that each cell expresses only the appropriate genes, duplicates its genome with high fidelity, divides only when required, and combats constant assaults on its DNA.

Failure in any of the mechanisms regulating these events can lead to a wide range of outcomes from altered developmental trajectories to complex diseases. Furthermore, a number of chromatin modifying proteins are involved in genetic susceptibility to diseases. The objective of our research is to understand the molecular mechanisms of epigenetic regulation in response to the environment. This is largely achieved through evaluating DNA methylation, histone variants, post-translational modification of histone, and nucleosome positioning. Additionally, genetic variation may interact with specific environments, imparting sensitivity or resilience, to ultimately alter epigenetics patterns and phenotypic outcomes.

Project Overview

In one facet of our research program, we study human population epigenetics aimed at deciphering the mechanisms by which environmental exposures and early-life experiences can “get under the skin” to regulate gene activity and contribute to health and disease across the life course. This research aligns with the Developmental Origins of Health and Disease (DOHaD) hypothesis, which postulates that the developmental period and early life are particularly sensitive periods where social or environmental insults can influence health long after the insult itself. Our findings support the model that early-life social and environmental factors, including stress and socioeconomic status, leave a biological footprint. We measure this biological embedding of early life exposures through epigenetic patterns and accompanying gene expression changes, many of which are maintained until adulthood and may influence future health. We have extensive interdisciplinary collaborations across Canada and around the world and are affiliated with multiple NCEs (including AllerGen and NeuroDevNet).

Rather than acting as an inert scaffold for DNA, dynamic and flexible chromatin structures and modifications have profound effects on almost all aspects of chromosome behaviour and genome function. Thus, the second objective of our research utilizes Saccharomyces cerevisiae as a model organism to tease apart the mechanisms responsible for the creation, regulation, and maintenance of the chromatin signature. These queries include how distinct chromosomal neighbourhoods are established, how they function and interact with enzymes involved in DNA metabolism, what functional differences exist between histone variants and canonical histones, and how chromatin-remodeling complexes are regulated. Currently, we focus on three distinct areas of chromatin biology: functional genomic characterization of chromatin-modifying complexes; DNA damage repair in the context of the chromatin template; and crosstalk between the RNAPII machinery and chromatin.

Together, the research in our lab bridges the molecular mechanisms of epigenetic regulation with the social and environmental determinants of human health to develop a comprehensive understanding of early life.

Selected Publications

Miller G.E., Chen E., Fok A.K., Walker H., Lim A., Nicholls E.F., Cole S., and Kobor M.S. (2009) Low Early-Life Social Class Leaves a Biological Residue Manifested by Decreased Glucocorticoid and Increased Proinflammatory Signaling. Proc Natl Acad Sci USA 106:14716-21.

Schulze JM, Jackson J, Nakanishi S, Gardner JM, Hentrich T, Haug J, Johnston M, Jaspersen SL, Kobor MS, Shilatifard A. (2009) Linking cell cycle to histone modifications: SBF and H2B monoubiquitination machinery and cell-cycle regulation of H3K79 dimethylation. Mol Cell 35(5):626-41.

Wang AY, Schulze JM, Skordalakes E, Gin JW, Berger JM, Rine J, Kobor MS. (2009) Asf1-like structure of the conserved Yaf9 YEATS domain and role in H2A.Z deposition and acetylation. Proc Natl Acad Sci USA 106(51):21573-8.

Chen E., Miller G.E., Kobor M.S., and Cole S.W. (2010) Maternal Warmth Buffers the Effects of Low Early-Life Socioeconomic Status on Pro-Inflammatory Signalling in Adulthood. Mol Psychiatry 16:729-37.

Lévesque N, Leung GP, Fok AK, Schmidt TI, Kobor MS. (2010) Loss of H3 K79 trimethylation leads to suppression of Rtt107-dependent DNA damage sensitivity through the translesion synthesis pathway. J Biol Chem 285(45):35113-22.

Yuen R.K., Neumann S.M., Fok A.F., Peñaherrera M.S., McFadden D.E., Robinson W.P., and Kobor M.S. (2011) Extensive Epigenetic Reprogramming in Human Somatic Tissues between Fetus and Adult.  Epigenetics Chromatin 4:7.

Essex M.J., Boyce W.T., Hertzman C., Lam L.L., Armstrong J.M., Neumann S.M., and Kobor M.S. (2011) Epigenetic Vestiges of Early Developmental Adversity: Childhood Stress Exposure and DNA Methylation in Adolescence. Child Dev 84:58-75.

Wang AY, Aristizabal MJ, Ryan C, Krogan NJ, Kobor MS. Key functional regions in the histone variant H2A.Z C-terminal docking domain. Mol Cell Biol 31(18):3871-84. (2011).

Fraser H.B., Lam L.L., Neumann S.M., and Kobor M.S. (2012) Population-specificity of Human DNA Methylation. Genome Biol 13:R8.

Lam L.L., Emberly E., Fraser H.B., Neumann S.M., Chen E., Miller G.E. and Kobor M.S. (2012) Factors Underlying Variable DNA Methylation in a Human Community Cohort. Proc Natl Acad Sci USA 109 Suppl 2:17253-60.

Aristizabal MJ, Negri GL, Benschop JJ, Holstege FC, Krogan NJ, Kobor MS. (2013) High-throughput genetic and gene expression analysis of the RNAPII-CTD reveals unexpected connections to SRB10/CDK8. PLoS Genet 9(8):e1003758.

Teh A.L., Pan H., Chen L., Ong M.L., Dogra S., Wong J., MacIsaac J.L., Mah S.M., McEwen L.M., Saw S.M., Godfrey K.M., Chong Y.S., Kwek K., Kwoh C.K., Soh S.E., Barton S., Karnani N., Cheong C.Y., Buschdorf J.P., Stunkel W., Kobor M.S., Meaney M.J., Gluckman P.D., and Holbrook J.D. (2014) The Effect of Genotype and in utero Environment on Inter-individual Variation in Neonate DNA Methylomes. Genome Res 24:1064-74.

Lu PY, Kobor MS. (2014) Maintenance of heterochromatin boundary and nucleosome composition at promoters by the Asf1 histone chaperone and SWR1-C chromatin remodeler in Saccharomyces cerevisiae. Genetics 197(1):133-45.

Boyce W.T., and Kobor M.S. (2015) Development and the Epigenome: The ‘Synapse’ of Gene – Environment Interplay. Dev Sci 18:1-23.

Chen L., Pan H. Tuan T.A., Teh A.L., MacIsaac J.L., Mah S.M., McEwen L.M., Li Y., Chen H., Broekman B.F., Buschdorf J.P., Chong Y.S., Kwek K., Saw S.M., Gluckman P.D., Fortier M.V., Rifkin-Graboi A., Kobor M.S., Qiu A., Meaney M.J., and Holbrook J.D; GUSTO Study Group. (2015) Brain-derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Influences the Association of the Methylome with Maternal Anxiety and Neonatal Brain Volumes. Dev Psychopathol 271:137-50.

Research Group Members

Maria Aristizabal, Postdoctoral Fellow

Sachini Ariyaratne, MSc Student

Josh Brown, PhD Candidate

Nicole Couto, PhD Candidate

Rachel Edgar, Research Assistant

Tanya Erb, Administrative Manager

Sarah Goodman, PhD Candidate

Sumaiya Islam, PhD Candidate

Meaghan Jones, Postdoctoral Fellow

Alyssa Kirlin, PhD Candidate

Phoebe Lu, Postdoctoral Fellow

Alexandre Lussier, PhD Student

Julie MacIsaac, Research Associate / Lab Manager

Lisa McEwen, PhD Student

Alexander Morin, Research Assistant

Mina Park, PhD Student

Olivia Wong, MSc Student