M Szyf

McGill University, Montréal, Quebec, Canada

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Publications (114)623.47 Total impact

  • Moshe Szyf
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    ABSTRACT: Advances in our understanding of the epigenetic mechanisms that control gene expression in the central nervous system (CNS) and their role in neuropsychiatric disorders are paving the way for a potential new therapeutic approach that is focused on reversing the epigenetic underpinnings of neuropsychiatric conditions. In this article, the complexity of epigenetic processes and the current level of proof for their involvement in CNS disorders are discussed. The preclinical evidence for efficacy of pharmacological approaches that target epigenetics in the CNS and the particular challenges of this approach are also examined. Finally, strategies to address these challenges through the development of improved evidence-based epigenetic therapeutics and through combining pharmacological and behavioural approaches are presented.
    dressNature Reviews Drug Discovery 05/2015; DOI:10.1038/nrd4580 · 37.23 Impact Factor
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    ABSTRACT: Hibernating mammals conserve energy in the winter by undergoing prolonged bouts of torpor, interspersed with brief arousals back to euthermia. These bouts are accompanied with a suite of reversible physiological and biochemical changes; however, much remains to be discovered about the molecular mechanisms involved. Given the seasonal nature of hibernation, it stands to reason that underlying plastic epigenetic mechanisms should exist. One such form of epigenomic regulation involves the reversible modification of cytosine bases in DNA by methylation. DNA methylation is well-known to be a mechanism that confers upon DNA its cellular identity during differentiation in response to innate developmental cues. However, it has recently been hypothesized that DNA methylation also acts as a mechanism for adapting genome function to changing external environmental and experiential signals over different time scales, including during adulthood. Here, we tested the hypothesis that DNA methylation is altered during hibernation in adult wild animals. This study evaluated global changes in DNA methylation in response to hibernation in the liver and skeletal muscle of thirteen-lined ground squirrels along with changes in expression of DNA methyltransferases (DNMT1/3B) and methyl binding domain proteins (MBDs). A reduction in global DNA methylation occurred in muscle during torpor phases whereas significant changes in DNMTs and MBDs were seen in both tissues. We also report dynamic changes in DNA methylation in the promoter of the myocyte enhancer factor 2C (mef2c) gene, a candidate regulator of metabolism in skeletal muscle. Taken together, these data show that genomic DNA methylation is dynamic across torpor-arousal bouts during winter hibernation, consistent with a role for this regulatory mechanism in contributing to the hibernation phenotype. © 2015. Published by The Company of Biologists Ltd.
    Journal of Experimental Biology 04/2015; 218(11). DOI:10.1242/jeb.116046 · 3.00 Impact Factor
  • Journal of Pain 04/2015; 16(4):S39. DOI:10.1016/j.jpain.2015.01.169 · 4.22 Impact Factor
  • Moshe Szyf
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    ABSTRACT: The idea that inherited genotypes define phenotypes has been paramount in modern biology. The question remains, however, whether stable phenotypes could be also inherited from parents outside the genetic sequence per se. Recent data suggests that parental experiences could be transmitted behaviorally, through in utero exposure of the developing fetus to the maternal environment, or through either the male or female germline. The challenge is delineating a plausible mechanism. In the last decade it has been proposed that epigenetic mechanisms are involved in multigenerational transmission of phenotypes and transgenerational inheritance. The prospect that ancestral experiences are written in our epigenome has immense implications to our understanding of human behavior, health and disease.
    Trends in Molecular Medicine 12/2014; 21(2). DOI:10.1016/j.molmed.2014.12.004 · 10.11 Impact Factor
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    ABSTRACT: We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
    Nature Neuroscience 08/2014; 17(9). DOI:10.1038/nn.3786 · 14.98 Impact Factor
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    ABSTRACT: During the perinatal period, the brain is particularly sensitive to remodelling by environmental factors. Adverse early life experiences, such as stress exposure or sub-optimal maternal care can have long-lasting detrimental consequences for an individual. This phenomenon is often referred to as ‘early-life programming’ and is associated with an increased risk of disease. Typically, rodents exposed to prenatal stress or postnatal maternal deprivation display enhanced neuroendocrine responses to stress, increased levels of anxiety and depressive-like behaviours and cognitive impairments. Some of the phenotypes observed in these models of early life adversity are likely to share common neurobiological mechanisms. For example, there is evidence for impaired glucocorticoid negative feedback control of the HPA axis, altered glutamate neurotransmission and reduced hippocampal neurogenesis in both prenatally stressed rats and rats that experienced deficient maternal care. The possible mechanisms through which maternal stress during pregnancy may be transmitted to the offspring are reviewed, with special consideration given to altered maternal behaviour postpartum. We also discuss what is known about the neurobiological and epigenetic mechanisms that underpin early life programming of the neonatal brain in the first generation and subsequent generations, with a view to abrogating programming effects and potentially identifying new therapeutic targets for the treatment of stress-related disorders and cognitive impairment.This article is protected by copyright. All rights reserved.
    Journal of Neuroendocrinology 07/2014; 26(10). DOI:10.1111/jne.12175 · 3.51 Impact Factor
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    ABSTRACT: Astrocytes are glial cells specific to the central nervous system and involved in numerous brain functions, including regulation of synaptic transmission and of immune reactions. There is mounting evidence suggesting astrocytic dysfunction in psychopathologies such as major depression, however, little is known about the underlying etiological mechanisms. Here we report a two-stage study investigating genome-wide DNA methylation associated with astrocytic markers in depressive psychopathology. We first characterized prefrontal cortex samples from 121 individuals (76 who died during a depressive episode and 45 healthy controls) for the astrocytic markers GFAP, ALDH1L1, SOX9, GLUL, SCL1A3, GJA1 and GJB6. A subset of 22 cases with consistently downregulated astrocytic markers was then compared with 17 matched controls using methylation binding domain-2 (MBD2) sequencing followed by validation with high-resolution melting and bisulfite Sanger sequencing. With these data, we generated a genome-wide methylation map unique to altered astrocyte-associated depressive psychopathology. The map revealed differentially methylated regions (DMRs) between cases and controls, the majority of which displayed reduced methylation levels in cases. Among intragenic DMRs, those found in GRIK2 (glutamate receptor, ionotropic kainate 2) and BEGAIN (brain-enriched guanylate kinase-associated protein) were most significant and also showed significant correlations with gene expression. Cell-sorted fractions were investigated and demonstrated an important non-neuronal contribution of methylation status in BEGAIN. Functional cell assays revealed promoter and enhancer-like properties in this region that were markedly decreased by methylation. Furthermore, a large number of our DMRs overlapped known Encyclopedia of DNA elements (ENCODE)-identified regulatory elements. Taken together, our data indicate significant differences in the methylation patterns specific to astrocytic dysfunction associated with depressive psychopathology, providing a potential framework for better understanding this disease phenotype.Molecular Psychiatry advance online publication, 25 March 2014; doi:10.1038/mp.2014.21.
    Molecular Psychiatry 03/2014; 20(3). DOI:10.1038/mp.2014.21 · 15.15 Impact Factor
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    ABSTRACT: Synthetic glucocorticoids (sGCs) are commonly prescribed for the management of inflammatory and endocrine disorders. However, nothing is known regarding the effects of sGC on adult germline methylome and whether these effects can be transmitted to the next generation. We hypothesized that administration of sGC to adult male mice alters DNA methylation in mature sperm and modifies the transcription and methylation of steroid receptors in male F1 offspring. Adult C57BL/6 males (n=10/group) were injected on 5 consecutive days with dexamethasone (sGC; 1mg/kg) or vehicle and euthanized 35 or 60 days after initial treatment or bred with control females (60 days post initial treatment; n=5/group). A significant increase in global non-CpG methylation was observed in F0 sperm 60 days following sGC treatment. In the hippocampus and kidney of postnatal (PND) 50 and PND240 male offspring derived from fathers exposed to sGC, significant differences in mineralocorticoid receptor (Nr3c2; Mr), estrogen alpha receptor (Nr3a1; Ers1) and glucocorticoid receptor (Nr3c1; Gr) expression were observed. Further, significant demethylation in regulatory regions of Mr, Gr, and Esr1 was observed in the PND50 kidney derived from fathers exposed to sGC. This is the first demonstration that paternal pharmacological exposure to sGC can alter the expression and DNA methylation of nuclear steroid receptors in brain and somatic tissues of offspring. These findings provide proof of principle that adult male exposure to sGC can affect DNA methylation and gene expression in offspring indicating the possibility that adult experiences that evoke increases in endogenous glucocorticoid (i.e. stress) might have similar effects.
    Biology of Reproduction 01/2014; 90(2). DOI:10.1095/biolreprod.113.115899 · 3.45 Impact Factor
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    ABSTRACT: Sleep is critical for normal brain function and mental health. However, the molecular mechanisms mediating the impact of sleep loss on both cognition and the sleep electroencephalogram remain mostly unknown. Acute sleep loss impacts brain gene expression broadly. These data contributed to current hypotheses regarding the role for sleep in metabolism, synaptic plasticity and neuroprotection. These changes in gene expression likely underlie increased sleep intensity following sleep deprivation (SD). Here we tested the hypothesis that epigenetic mechanisms coordinate the gene expression response driven by SD. We found that SD altered the cortical genome-wide distribution of two major epigenetic marks: DNA methylation and hydroxymethylation. DNA methylation differences were enriched in gene pathways involved in neuritogenesis and synaptic plasticity, whereas large changes (>4000 sites) in hydroxymethylation where observed in genes linked to cytoskeleton, signaling and neurotransmission, which closely matches SD-dependent changes in the transcriptome. Moreover, this epigenetic remodeling applied to elements previously linked to sleep need (for example, Arc and Egr1) and synaptic partners of Neuroligin-1 (Nlgn1; for example, Dlg4, Nrxn1 and Nlgn3), which we recently identified as a regulator of sleep intensity following SD. We show here that Nlgn1 mutant mice display an enhanced slow-wave slope during non-rapid eye movement sleep following SD but this mutation does not affect SD-dependent changes in gene expression, suggesting that the Nlgn pathway acts downstream to mechanisms triggering gene expression changes in SD. These data reveal that acute SD reprograms the epigenetic landscape, providing a unique molecular route by which sleep can impact brain function and health.
    Translational Psychiatry 01/2014; 4(1):e347. DOI:10.1038/tp.2013.120 · 4.36 Impact Factor
  • Moshe Szyf
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    ABSTRACT: Aberrant changes in gene function are believed to be involved in a wide spectrum of human disease including behavioral, cognitive and neurodegenerative pathologies. Most of the attention in the last few decades has focused on changes in gene sequence as a cause of gene dysfunction leading to disease and mental health disorders. Germ line mutations or other alterations in the sequence of DNA that associate with different behavioral and neurological pathologies have been identified. However, sequence alterations explain only a small faction of the cases. In addition there is evidence for “gene- environment” interactions in the brain suggesting mechanisms that alter gene function and the phenotype through environmental exposure. Genes are programmed by “epigenetic” mechanisms such as chromatin structure, chromatin modification and DNA methylation. These mechanisms confer on similar sequences different identities during cellular differentiation. Epigenetic differences are proposed to be involved in differentiating gene function in response to different environmental contexts and could result in alterations in functional gene networks that lead to brain disease. Epigenetic markers could serve important biomarkers in brain and behavioral diseases. Moreover, epigenetic processes are potentially reversible pointing to epigenetic therapeutics in psychotherapy.
    European Neuropsychopharmacology 01/2014; 25(5). DOI:10.1016/j.euroneuro.2014.01.009 · 5.40 Impact Factor
  • Moshe Szyf
    Nature Neuroscience 12/2013; 17(1):2-4. DOI:10.1038/nn.3603 · 14.98 Impact Factor
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    ABSTRACT: DNA-methyltransferases (DNMTs) are a class of epigenetic enzymes that catalyze the transfer of a methyl moiety from the methyl donor S-adenosyl-L-methionine onto the C5 position of cytosine in DNA. This process is dysregulated in cancers and leads to the hypermethylation and silencing of tumor suppressor genes. The development of potent and selective inhibitors of DNMTs is of utmost importance for the discovery of new therapies for the treatment of cancer. We report herein the synthesis and DNMT inhibitory activity of 29 analogues derived from NSC 319745. The effect of selected compounds on the methylation level in the MDA-MB-231 human breast cancer cell line was evaluated using a luminometric methylation assay. Molecular docking studies have been conducted to propose a binding mode for this series.
    Medicinal Chemistry Communication 09/2013; 4(12):1562. DOI:10.1039/c3md00214d · 2.63 Impact Factor
  • Moshe Szyf
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    ABSTRACT: The relationship between innate, inborn inherited properties and the environment, particularly the social environment, has been one of the most contentious topics in human intellectual discourse for many generations. This discussion touches upon foundational moral and philosophical questions that define who we are, and is therefore highly emotionally loaded. This agelong discussion has been reinvigorated in recent times by leapfrog progress in genetic research and the emerging dominant dogma in biology that genotypes determine physical as well as behavioral phenotypes. The sequencing of the human genome and the increasing feasibility of whole genome sequencing raised hopes that the vast majority of human disorders and interindividual variation in health and behavior will be explained by interindividual variations in DNA sequence. Genetic determinism has been pervasively dominant in biological sciences for the last century and beyond. Strong evidence for heritability of behavioral traits has paved a path for these concepts into social and behavioral sciences as well. (Am J Public Health. Published online ahead of print August 8, 2013: e1-e3. doi:10.2105/AJPH.2013.301533).
    American Journal of Public Health 08/2013; DOI:10.2105/AJPH.2013.301533 · 4.23 Impact Factor
  • Moshe Szyf
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    ABSTRACT: The impact of early physical and social environments on life-long phenotypes is well known. Moreover, we have documented evidence for gene-environment interactions where identical gene variants are associated with different phenotypes that are dependent on early life adversity. What are the mechanisms that embed these early life experiences in the genome? DNA methylation is an enzymatically-catalyzed modification of DNA that serves as a mechanism by which similar sequences acquire cell type identity during cellular differentiation and embryogenesis in the same individual. The hypothesis that will be discussed here proposes that the same mechanism confers environmental-exposure specific identity upon DNA providing a mechanism for embedding environmental experiences in the genome, thus affecting long-term phenotypes. Particularly important is the environment early in life including both the prenatal and postnatal social environments.
    Journal of Genetics and Genomics 07/2013; 40(7):331-8. DOI:10.1016/j.jgg.2013.06.004 · 2.92 Impact Factor
  • 60th Annual Scientific Meeting of the; 03/2013
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    ABSTRACT: The late-gestation surge in fetal plasma cortisol is critical for maturation of fetal organ systems. As a result, synthetic glucocorticoids (sGCs) are administered to pregnant women at risk of delivering preterm. However, animal studies have shown that fetal exposure to sGC results in increased risk of behavioral, endocrine, and metabolic abnormalities in offspring. Here, we test the hypothesis that prenatal GC exposure resulting from the fetal cortisol surge or after sGC exposure results in promoter-specific epigenetic changes in the hippocampus. Fetal guinea pig hippocampi were collected before (gestational day [GD52]) and after (GD65) the fetal plasma cortisol surge (Term∼GD67) and 24 hours after (GD52) and 14 days after (GD65) two repeat courses of maternal sGC (betamethasone) treatment (n = 3-4/gp). We identified extensive genome-wide alterations in promoter methylation in late fetal development (coincident with the fetal cortisol surge), whereby the majority of the affected promoters exhibited hypomethylation. Fetuses exposed to sGC in late gestation exhibited substantial differences in DNA methylation and histone h3 lysine 9 (H3K9) acetylation in specific gene promoters; 24 hours after the sGC treatment, the majority of genes affected were hypomethylated or hyperacetylated. However, 14 days after sGC exposure these differences did not persist, whereas other promoters became hypermethylated or hyperacetylated. These data support the hypothesis that the fetal GC surge is responsible, in part, for significant variations in genome-wide promoter methylation and that prenatal sGC treatment profoundly changes the epigenetic landscape, affecting both DNA methylation and H3K9 acetylation. This is important given the widespread use of sGC in the management of women in preterm labor.
    Endocrinology 02/2013; 154(3). DOI:10.1210/en.2012-1980 · 4.64 Impact Factor
  • Moshe Szyf
    Nature Neuroscience 01/2013; 16(1):2-4. DOI:10.1038/nn.3286 · 14.98 Impact Factor
  • M. Szyf
    European Neuropsychopharmacology 10/2012; 22:S124. DOI:10.1016/S0924-977X(12)70143-8 · 5.40 Impact Factor
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    Moshe Szyf, Johanna Bick
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    ABSTRACT: Although epidemiological data provide evidence that early life experience plays a critical role in human development, the mechanism of how this works remains in question. Recent data from human and animal literature suggest that epigenetic changes, such as DNA methylation, are involved not only in cellular differentiation but also in the modulation of genome function in response to early life experience affecting gene function and the phenotype. Such modulations may serve as a mechanism for life-long genome adaptation. These changes seem to be widely distributed across the genome and to involve central and peripheral systems. Examining the environmental circumstances associated with the onset and reversal of DNA methylation will be critical for understanding risk and resiliency.
    Child Development 08/2012; 84(1). DOI:10.1111/j.1467-8624.2012.01793.x · 4.92 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):4028-4028. DOI:10.1158/1538-7445.AM2012-4028 · 9.28 Impact Factor

Publication Stats

5k Citations
623.47 Total Impact Points

Institutions

  • 1991–2015
    • McGill University
      • • Department of Pharmacology and Therapeutics
      • • Department of Psychiatry
      Montréal, Quebec, Canada
  • 1989–1992
    • Harvard Medical School
      • Department of Genetics
      Boston, MA, United States
    • University of Toronto
      Toronto, Ontario, Canada
  • 1982–1987
    • Hebrew University of Jerusalem
      • Department of Biochemistry and Molecular Biology
      Yerushalayim, Jerusalem District, Israel
  • 1986
    • National Institute of Mental Health (NIMH)
      Maryland, United States