M Szyf

McGill University, Montréal, Quebec, Canada

Are you M Szyf?

Claim your profile

Publications (98)461.1 Total impact

  • [Show abstract] [Hide abstract]
    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;
  • Source
    [Show abstract] [Hide abstract]
    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; · 15.15 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 4.03 Impact Factor
  • Moshe Szyf
    [Show abstract] [Hide abstract]
    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;
  • Source
    [Show abstract] [Hide abstract]
    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:e347.
  • Moshe Szyf
    Nature Neuroscience 12/2013; 17(1):2-4. · 15.25 Impact Factor
  • Moshe Szyf
    [Show abstract] [Hide abstract]
    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; · 3.93 Impact Factor
  • Moshe Szyf
    [Show abstract] [Hide abstract]
    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. · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    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; · 4.72 Impact Factor
  • Moshe Szyf
    Nature Neuroscience 01/2013; 16(1):2-4. · 15.25 Impact Factor
  • Source
    Moshe Szyf, Johanna Bick
    [Show abstract] [Hide abstract]
    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; · 4.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prenatal synthetic glucocorticoids (sGC) are administered to pregnant women at risk of delivering preterm, approximately 10% of all pregnancies. Animal studies have demonstrated that offspring exposed to elevated glucocorticoids, either by administration of sGC or as a result of maternal stress, are at increased risk of developing behavioral, endocrine, and metabolic abnormalities. DNA methylation is a covalent modification of DNA that plays a critical role in long-lasting programming of gene expression. Here we tested the hypothesis that prenatal sGC treatment has both acute and long-term effects on DNA methylation states in the fetus and offspring and that these effects extend into a subsequent generation. Pregnant guinea pigs were treated with sGC in late gestation, and methylation analysis by luminometric methylation assay was undertaken in organs from fetuses and offspring across two generations. Expression of genes that modify the epigenetic state were measured by quantitative real-time PCR. Results indicate that there are organ-specific developmental trajectories of methylation in the fetus and newborn. Furthermore, these trajectories are substantially modified by intrauterine exposure to sGC. These sGC-induced changes in DNA methylation remain into adulthood and are evident in the next generation. Furthermore, prenatal sGC exposure alters the expression of several genes encoding proteins that modulate the epigenetic state. Several of these changes are long lasting and are also present in the next generation. These data support the hypothesis that prenatal sGC exposure leads to broad changes in critical components of the epigenetic machinery and that these effects can pass to the next generation.
    Endocrinology 05/2012; 153(7):3269-83. · 4.72 Impact Factor
  • Source
    Moshe Szyf
    [Show abstract] [Hide abstract]
    ABSTRACT: Changes in gene expression that reset a cell program from a normal to a diseased state involve multiple genetic circuitries, creating a characteristic signature of gene expression that defines the cell's unique identity. Such signatures have been demonstrated to classify subtypes of breast cancers. Because DNA methylation is critical in programming gene expression, a change in methylation from a normal to diseased state should be similarly reflected in a signature of DNA methylation that involves multiple gene pathways. Whole-genome approaches have recently been used with different levels of success to delineate breast-cancer-specific DNA methylation signatures, and to test whether they can classify breast cancer and whether they could be associated with specific clinical outcomes. Recent work suggests that DNA methylation signatures will extend our ability to classify breast cancer and predict outcome beyond what is currently possible. DNA methylation is a robust biomarker, vastly more stable than RNA or proteins, and is therefore a promising target for the development of new approaches for diagnosis and prognosis of breast cancer and other diseases. Here, I review the scientific basis for using DNA methylation signatures in breast cancer classification and prognosis. I discuss the role of DNA methylation in normal gene regulation, the aberrations in DNA methylation in cancer, and candidate-gene and whole-genome approaches to classify breast cancer subtypes using DNA methylation markers.
    Genome Medicine 03/2012; 4(3):26. · 4.94 Impact Factor
  • Moshe Szyf
    Epigenomics 02/2012; 4(1):13-4. · 2.43 Impact Factor
  • M Szyf
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA methylation is a chemical modification of DNA that confers, upon identical sequences, different identities that are reflected in different gene expression programming. DNA methylation has a well-established role in cellular differentiation by providing a mechanism for one genome to express multiple phenotypes in a multicellular organism. Recent data point however to the possibility that in addition to the innate process of cellular differentiation, DNA methylation can serve as a genome adaptation mechanism, adapting genome function to changing environmental contexts including social environments. A critical time point for this process is early life when cues from the social and physical environments define lifelong trajectories of physical and mental health. DNA methylation and additional epigenetic modifications could therefore serve as molecular links between 'nurture' and 'nature'. Data that are consistent with this new role for DNA methylation as a mechanism for conferring an 'environment' specific identity to DNA will be discussed.
    Clinical Genetics 01/2012; 81(4):341-9. · 4.25 Impact Factor
  • Moshe Szyf
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA methylation is an enzymatic modification of the DNA molecule that confers unique differential identities upon similar DNA sequences. DNA methylation plays a critical role in cellular differentiation by conferring cell-type identity upon differentiated tissues in multicellular organisms by an innate developmentally programmed process. Recent data points to the possibility that DNA methylation plays a role in responding to external cues and conferring environment-context identity to DNA. DNA methylation is implicated in the response to early life social environment and might be playing an important role in setting up stable behavioral phenotypes in response to early-life social environment. The critical question is whether these responses are limited to the brain or involve the immune system as well. Addressing this question has important implications on understanding the mechanisms involved in DNA methylation mediated responses to the environment and how they impact the phenotype as well as on the possibility of studying the associations between DNA methylation and behavior and behavioral pathologies in living humans. A model is presented suggesting that DNA methylation acts as a mechanism of genome adaptation to the environment that is genomewide and systemwide. New data suggesting associations between DNA methylation patterns in white blood cells and the social environment will be discussed.
    Progress in allergy 01/2012; 98:85-99.
  • Moshe Szyf
    Reproductive Toxicology - REPROD TOXICOL. 01/2011; 31(2):249-249.
  • [Show abstract] [Hide abstract]
    ABSTRACT: At diagnosis, Alzheimer's disease (AD) brains are extensively burdened with plaques and tangles and display a degree of synaptic failure most likely beyond therapeutic treatment. It is therefore crucial to identify early pathological events in the progression of the disease. While it is not currently feasible to identify and study early, pre-clinical stages of AD, transgenic (Tg) models offer a valuable tool in this regard. Here we investigated cognitive, structural and biochemical CNS alterations occurring in our newly developed McGill-Thyl-APP Tg mice (over-expressing the human amyloid precursor protein with the Swedish and Indiana mutations) prior to extracellular plaque deposition. Pre-plaque, 3-month old Tg mice already displayed cognitive deficits concomitant with reorganization of cortical cholinergic pre-synaptic terminals. Conformational specific antibodies revealed the early appearance of intracellular amyloid β (Aβ)-oligomers and fibrillar oligomers in pyramidal neurons of cerebral cortex and hippocampus. At the same age, the cortical levels of insulin degrading enzyme -a well established Aβ-peptidase, were found to be significantly down-regulated. Our results suggest that, in the McGill-Thy1-APP Tg model, functional, structural and biochemical alterations are already present in the CNS at early, pre-plaque stages of the pathology. Accumulation of intraneuronal neurotoxic Aβ-oligomers (possibly caused by a failure in the clearance machinery) is likely to be the culprit of such early, pre-plaque pathology. Similar neuronal alterations might occur prior to clinical diagnosis in AD, during a yet undefined 'latent' stage. A better understanding of such pre-clinical AD might yield novel therapeutic targets and or diagnostic tools.
    Current Alzheimer research 12/2010; 8(1):4-23. · 4.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
    Endocrine reviews 10/2010; 32(2):159-224. · 19.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A sub-optimal intrauterine environment alters the trajectory of fetal development with profound effects on life-time health. Altered methylation, a proposed epigenetic mechanism responsible for these changes, has been studied in non-primate species but not nonhuman primates. We tested the hypotheses that global methylation in fetal baboon demonstrates organ specificity, gestational age specificity, and changes with maternal nutritional status. We measured global DNA methylation in fetuses of control fed (CTR) and nutrient restricted mothers fed 70% of controls (MNR) for brain, kidney, liver and heart at 0.5 and 0.9 gestation (G). We observed organ and gestation specific changes that were modified by maternal diet. Methylation in CTR fetuses was highest in frontal cortex and lowest in liver. MNR decreased methylation in 0.5G kidney and increased methylation in 0.9G kidney and frontal cortex. These results demonstrate a potential epigenetic mechanism whereby reduced maternal nutrition has long-term programming effects on fetal organ development.
    Journal of Medical Primatology 09/2009; 38(4):219-27. · 1.11 Impact Factor

Publication Stats

3k Citations
461.10 Total Impact Points

Institutions

  • 1991–2014
    • McGill University
      • Department of Pharmacology and Therapeutics
      Montréal, Quebec, Canada
  • 2012
    • Yale University
      New Haven, Connecticut, United States
  • 2007
    • Université de Montréal
      • Montreal University Health Centre
      Montréal, Quebec, Canada
  • 1989–1992
    • Harvard Medical School
      • Department of Genetics
      Boston, MA, United States
  • 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