Michael Kobor

Professor

Research Interests

Epigenetics
Social Epigenetics
molecular biology
Chromatin Biology

Relevant Degree Programs

 

Recruitment

Master's students
Doctoral students
Postdoctoral Fellows
Any time / year round
I am open to hosting Visiting International Research Students (non-degree, up to 12 months).

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Nov 2019)
Contributions of intrinsic and environmental factors to early life DNA methylation (2019)

Many early experiences and exposures are known to cause health disparities later in life, suggesting that they are somehow ‘biologically embedded’. The mechanisms underlying ‘biological embedding’ are currently not well understood. However, emerging evidence has implicated a potential contribution from epigenetic modifications, such as DNA methylation (DNAm), which has been shown to associate with early life experiences of low socioeconomic status. Additional related experiences have also been connected with DNAm, including parental stress, childhood maltreatment or deprivation, and maternal mental health problems during the perinatal period. The relationship between early life experience and epigenetics is complicated by internal psychological and physiological factors, as well as genetic variation, which can account for 20% to 80% of inter-individual epigenetic differences. As well, stress reactivity and temperament are predictive of how a child may interact with his or her environment and can affect how such exposures are internalized. Thus, the main objectives of my dissertation were to elucidate the relationships between childhood environment, DNAm, genetic variation, and behaviour, to understand how these systems influence one another. Using matched DNAm profiles from blood and buccal tissue from a cross-sectional cohort of Canadian children, I uncovered tissue-specific and -shared DNAm signatures in order to glean the utility of accessible tissues in epigenetic association studies. In a longitudinal cohort, I tested the hypothesis that indicators of children’s early internal, biological and behavioural responses to stressful challenges are linked to stable patterns of DNAm later in life; I found relationships between biobehavioural response propensities in early life and patterns of DNAm in DLX5 and IGF2 genes at ages 15 and 18. Finally, I examined the epigenetic correlates of familial socioeconomic status in matched childhood peripheral blood and dried neonatal blood spot samples, allowing me to assess the DNAm pattern over time. Together these findings build upon our current understanding of the role of DNAm in biological embedding and more broadly, the field of social epigenetics.

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DNA methylation variation across the human life course (2018)

Aging is a multifaceted process occurring in all living organisms, and it involves the breakdown of biological robustness. Although much research has revealed fascinating features of cellular mechanisms related to aging and lifespan, we have yet to understand the underpinnings driving this inevitable progression. Epigenetics is one area of aging research that has developed significant interest as certain modifications, such as DNA methylation, have been proposed to mediate the relationship between the environment and gene expression as well as have age-associated patterns. Interestingly, predictors of age based on DNA methylation of
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Tissue-specific investigations of DNA methylation variation in human neurobiological diseases (2018)

Epigenomic variation represents an emerging focus in human health research, particularly in regards to neurobiological disease susceptibility and pathogenesis. DNA methylation (DNAm), which involves the covalent attachment of a methyl group to a cytosine primarily at CpG dinucleotides, has been widely assessed in the context of epigenome-wide association studies (EWASs), with DNAm associations identified across a broad range of disease states, environmental exposures and genetic backgrounds. However, DNAm profiling in neurobiological diseases is challenged by the fact that DNAm variation is highly tissue-specific and target brain tissues may be difficult or impossible to collect from postmortem samples, in living individuals undergoing treatment interventions or in pediatric populations. As such, the use of cell-culture models or accessible peripheral tissues such as blood or buccal swabs represent alternative approaches used in human neurobiological DNAm studies to identify potential biomarkers of disease or treatment response. The overarching aim of my dissertation was to apply and evaluate various tissue-specific approaches to investigate DNAm variation across different neurobiological diseases. To this end, I performed four separate studies to assess disease-associated DNAm from a) post-mortem brain samples, b) primary brain-derived cell culture models and c) accessible peripheral tissues. Specifically, I examined DNAm patterns related to Huntington’s disease pathogenesis and tissue-specific Huntingtin gene expression in postmortem human cortex samples. I subsequently compared DNAm profiles from glioblastoma multiforme tumours and matched primary cell cultures enriched for brain-tumour initiating cell populations, identifying a homeobox-enriched signature of differential DNAm between the paired samples. Beyond brain-specific DNAm patterns, I also explored the use of a disease-relevant blood cell type, CD³⁺ T-lymphocytes, to detect DNAm alterations associated with alcohol dependence in patients undergoing a clinical intervention. Finally, I assessed DNAm variability and the influence of genetic variation on DNAm in peripheral blood and buccal epithelial cells from two pediatric cohorts, highlighting a number of potential considerations and practical implications for the appropriate design and interpretation of early-life EWAS analyses in these tissues. Overall, these findings provide evidence to implicate DNAm variation in neurological function and pathology as well as present potential opportunities for the identification of novel biomarkers in accessible tissues.

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Epigenetic signatures of prenatal alcohol exposure (2017)

Prenatal alcohol exposure (PAE) can alter the development, function, and regulation of neurobiological and physiological systems, causing lasting cognitive alterations, behavioral deficits, immune dysfunction, and increased vulnerability to mental health problems. In humans, the spectrum of these deficits is known as fetal alcohol spectrum disorder (FASD). Although the molecular underpinnings are not fully elucidated, epigenetic mechanisms are a prime candidate for the programming of physiological systems by PAE, as they may bridge environmental stimuli and neurodevelopmental outcomes. DNA methylation is also emerging as a potential biomarker of early-life events, which may aid in earlier FASD diagnoses. Thus, my overarching aim was to identify epigenetic mechanisms that may contribute to the deficits associated with FASD and act as biosignatures of PAE. Specifically, I used genome-wide approaches to assess underlying gene expression programs and epigenomic profiles in a rat model of PAE and clinical cohorts of individuals with FASD. In the rat model, I identified alterations to gene expression programs in the brain of adult PAE females under steady-state and immune challenge conditions. Building on these long-term alterations to transcriptomic programs, I identified altered DNA methylation patterns persisting from birth to weaning in the hypothalamus PAE animals, suggestive of early reprogramming of neurobiological systems. In parallel, I found concordant alterations to DNA methylation profiles in the hypothalamus and white blood cells of PAE animals, which may reflect systemic effects and potential biomarkers of PAE. To complement the animal model, I also investigated DNA methylation patterns in two clinical cohorts of FASD, where I identified an epigenetic signature of FASD in buccal epithelial cells. As these results raised the possibility of an epigenetic biomarker, I investigated the relevance of DNA methylation as a diagnostic method for PAE, and successfully generated a predictive algorithm that could classify individuals with FASD versus controls. Overall, these findings provide evidence for the biological embedding of PAE’s effects through changes in gene expression and DNA methylation, while setting the stage for the development of novel biomarkers. Ultimately, these may aid in the development of targeted interventions and early screening tools to mitigate the deficits associated with FASD.

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Diverse mechanisms of transcription regulation by RNA polymerase II in saccharomyces ceresisiae (2015)

No abstract available.

Functional characterization of Rtt107 in the DNA damage response in Saccharomyces cerevisiae (2014)

No abstract available.

Deciphering the function of chromatin modifiers in genome regulation and maintenance in saccharomyces cerevisiae (2012)

No abstract available.

Genome-wide analysis of chromatin modification patterns and their functional associations with major cellular processes in Saccharomyces cerevisiae (2010)

No abstract available.

Master's Student Supervision (2010 - 2018)
Genome-wide analysis of DNA methylation variance in healthy human subjects (2015)

DNA methylation is a type of epigenetic modification that modulates gene expression by acting as an intermediate between genes and environment; this in turn could trigger phenotypic changes with widespread implications in both disease and population models. Unlike DNA sequence, which is relatively stable and finite, DNA methylation presents itself differently in different tissues, and it is described as the sum of interactions affecting attachment of methyl groups to DNA mostly as a result of development and aging, with minor influences from stochastic variability, and environmental factors. Most studies involving DNA methylation focus on finding epigenetic changes related to pathogenicity or disease, as a result, there are certain foundational questions that remain unanswered. In order to translate the current knowledge into reliable insights, it is important to answer these questions, then standardize research methods and establish reference epigenomes. Here we begin to address this challenge through two avenues: epigenomic characterization and environmental interaction. To characterize the epigenome, we monitored the peripheral blood mononuclear cell DNA methylation levels from healthy subjects over a circadian day, a month, and under prolonged sample storage. We also investigated tissue specific variability in DNA methylation by comparing matched peripheral blood mononuclear and buccal epithelial cell samples from healthy subjects. Lastly, we analyzed the impact of diesel exhaust on the DNA methylation. We discovered that while overall DNA methylation was stable within a circadian day, certain loci demonstrated significant changes over the course of a month. Prolonged sample storage, on the other hand, had an even larger effect on DNA methylation. When we compared differences across tissues, we found that although both tissues showed extensive probe-wise variability, the specific regions and magnitude of that variability differed strongly between tissues. Lastly, in light of environmental influences, we observed that DNA methylation was sensitive to even short-term exposure to diesel exhaust, and we identified associated CpG sites across the functional genome, as well as in Alu and LINE1 repetitive elements, with most of these exposure sensitive sites demonstrating loss of DNA methylation.

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