154 results on '"Szyf, Moshe"'
Search Results
2. Are the Healthy Vulnerable? Cytomegalovirus Seropositivity in Healthy Adults Is Associated With Accelerated Epigenetic Age and Immune Dysregulation.
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Poloni, Chad, Szyf, Moshe, Cheishvili, David, and Tsoukas, Christos M
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CORONAVIRUS diseases , *COVID-19 , *OLDER people , *SEROCONVERSION , *CYTOMEGALOVIRUSES , *CYTOMEGALOVIRUS diseases , *CYTOMEGALOVIRUS disease diagnosis , *RESEARCH , *EVALUATION research , *DNA methylation , *COMPARATIVE studies , *GENES , *RESEARCH funding , *T cells - Abstract
Background: Evaluating age as a risk factor for susceptibility to infectious diseases, particularly coronavirus disease 2019 (COVID-19), is critical. Cytomegalovirus (CMV) serologic prevalence increases with age and associates with inflammatory-mediated diseases in the elderly. However, little is known regarding the subclinical impact of CMV and risk it poses to healthy older adults. Prior to the COVID-19 pandemic we conducted a study to determine the association of CMV to biologic age and immune dysregulation.Methods: Community-dwelling, healthy adults older than 60 years were evaluated using DNA methylation assays to define epigenetic age (EpiAge) and T-cell immunophenotyping to assess immune dysregulation.Results: All subjects were healthy and asymptomatic. Those CMV seropositive had more lymphocytes, CD8 T cells, CD28- T cells, decreased CD4:CD8 cell ratios, and had higher average EpiAge (65.34 years) than those CMV seronegative (59.53 years). Decreased percent CD4 (P = .003) and numbers of CD4 T cells (P = .0199) correlated with increased EpiAge.Conclusions: Our novel findings distinguish altered immunity in the elderly based on CMV status. Chronic CMV infection in healthy, older adults is associated with indicators of immune dysregulation, both of which correlate to differences in EpiAge. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control.
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Patra, Samir Kumar and Szyf, Moshe
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COVID-19 , *DISEASE progression , *EPIGENETICS , *MEMBRANE lipids , *METABOLIC regulation , *VIRUS diseases - Abstract
COVID-19 has caused numerous deaths as well as imposed social isolation and upheaval world-wide. Although, the genome and the composition of the virus, the entry process and replication mechanisms are well investigated from by several laboratories across the world, there are many unknown remaining questions. For example, what are the functions of membrane lipids during entry, packaging and exit of virus particles? Also, the metabolic aspects of the infected tissue cells are poorly understood. In the course of virus replication and formation of virus particles within the host cell, the enhanced metabolic activities of the host is directly proportional to viral loads. The epigenetic landscape of the host cells is also altered, particularly the expression/repression of genes associated with cellular metabolism as well as cellular processes that are antagonistic to the virus. Metabolic pathways are enzyme driven processes and the expression profile and mechanism of regulations of the respective genes encoding those enzymes during the course of pathogen invasion might be highly informative on the course of the disease. Recently, the metabolic profile of the patients' sera have been analysed from few patients. In view of this, and to gain further insights into the roles that epigenetic mechanisms might play in this scenario in regulation of metabolic pathways during the progression of COVID-19 are discussed and summarised in this contribution for ensuring best therapy. • The genome and the composition of the COVID-19 virus, SARS-CoV-2 are known. • Role of membrane lipids during entry, packaging and exit of virus particles not well characterized. • The metabolic aspects of the infected tissue cells are poorly understood. • The epigenetic landscape of the host cells alters during COVID-19. • The roles that epigenetic mechanisms might play in this scenario is discussed and summarised for ensuring best therapy. [ABSTRACT FROM AUTHOR]
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- 2022
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4. DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli.
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Frodl, Thomas, Szyf, Moshe, Carballedo, Angela, Ly, Victoria, Dymov, Sergiy, Vaisheva, Farida, Morris, Derek, Fahey, Ciara, Meaney, James, Gill, Michael, and Booij, Linda
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BRAIN physiology , *DNA , *ANALYSIS of covariance , *CHI-squared test , *MENTAL depression , *EMOTIONS , *GENES , *REGRESSION analysis , *RESEARCH funding , *SEROTONIN , *STATISTICS , *DATA analysis , *CASE-control method , *DATA analysis software , *DESCRIPTIVE statistics , *PHYSIOLOGY - Abstract
Background: The aim of the present study was to investigate the association of fMRI blood oxygen--level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD). Methods: We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyro-sequencing. Results: Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation. Limitations: It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn. Conclusion: Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery. [ABSTRACT FROM AUTHOR]
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- 2015
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5. Prospects for the development of epigenetic drugs for CNS conditions.
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Szyf, Moshe
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EPIGENETICS , *GENE expression , *NEUROBEHAVIORAL disorders , *GENE mapping , *DNA methylation , *PHARMACEUTICAL research , *THERAPEUTICS , *CENTRAL nervous system diseases - 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. [ABSTRACT FROM AUTHOR]
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- 2015
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6. Epigenetics, a key for unlocking complex CNS disorders? Therapeutic implications.
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Szyf, Moshe
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EPIGENETICS , *CENTRAL nervous system diseases , *THERAPEUTICS , *DRUG monitoring , *NUCLEOTIDE sequencing , *DNA methylation , *PSYCHOTHERAPY , *GENETICS - 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 last few decades have 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 fraction 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. [ABSTRACT FROM AUTHOR]
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- 2015
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7. DNA Methylation of the Serotonin Transporter Gene in Peripheral Cells and Stress-Related Changes in Hippocampal Volume: A Study in Depressed Patients and Healthy Controls.
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Booij, Linda, Szyf, Moshe, Carballedo, Angela, Frey, Eva-Maria, Morris, Derek, Dymov, Sergiy, Vaisheva, Farida, Ly, Victoria, Fahey, Ciara, Meaney, James, Gill, Michael, and Frodl, Thomas
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SEROTONIN transporters , *HIPPOCAMPUS physiology , *DEPRESSED persons , *ETIOLOGY of diseases , *NEURAL development , *PATHOLOGICAL psychology - Abstract
Serotonin plays an important role in the etiology of depression. Serotonin is also crucial for brain development. For instance, animal studies have demonstrated that early disruptions in the serotonin system affect brain development and emotion regulation in later life. A plausible explanation is that environmental stressors reprogram the serotonin system through epigenetic processes by altering serotonin system gene expression. This in turn may affect brain development, including the hippocampus, a region with dense serotonergic innervations and important in stress-regulation. The aim of this study was to test whether greater DNA methylation in specific CpG sites at the serotonin transporter promoter in peripheral cells is associated with childhood trauma, depression, and smaller hippocampal volume. We were particularly interested in those CpG sites whose state of methylation in peripheral cells had previously been associated with in vivo measures of brain serotonin synthesis. Thirty-three adults with Major Depressive Disorder (MDD) (23 females) and 36 matched healthy controls (21 females) were included in the study. Depressive symptoms, childhood trauma, and high-resolution structural MRI for hippocampal volume were assessed. Site-specific serotonin transporter methylation was assessed using pyrosequencing. Childhood trauma, being male, and smaller hippocampal volume were independently associated with greater peripheral serotonin transporter methylation. Greater serotonin transporter methylation in the depressed group was observed only in SSRI-treated patients. These results suggest that serotonin transporter methylation may be involved in physiological gene-environment interaction in the development of stress-related brain alterations. The results provide some indications that site-specific serotonin transporter methylation may be a biomarker for serotonin-associated stress-related psychopathology. [ABSTRACT FROM AUTHOR]
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- 2015
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8. Nongenetic inheritance and transgenerational epigenetics.
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Szyf, Moshe
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EPIGENETICS , *PHENOTYPES , *DNA methylation , *HUMAN heredity , *MEDICAL genetics , *GENOMES - 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 independently of the genetic sequence per se . Recent data suggest that parental experiences can 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 to delineate a plausible mechanism. In the past 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 for our understanding of human behavior, health, and disease. [ABSTRACT FROM AUTHOR]
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- 2015
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9. The Genome- and System-Wide Response of DNA Methylation to Early Life Adversity and Its Implication on Mental Health.
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Szyf, Moshe
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DNA methylation , *MENTAL health , *PHENOTYPES , *PSYCHOLOGICAL stress , *SOCIAL context , *EPIGENETICS - Abstract
Early life adversity is associated with long-tem impacts on behaviour and physical and mental health. The mechanisms mediating the impact of early life environment on the phenotype are proposed to involve a change in the state of deoxyribonucleic acid (DNA) methylation and, as a consequence, in the stable programming of gene expression. Recent studies suggest that the changes in DNA methylation affect broad genomic regions, as well as peripheral tissues in addition to brain regions. Although the data are still scarce, it points to the possibility that DNA methylation is a mechanism of genome adaptation to signals from early life social environment. This modulation of the DNA methylation pattern is proposed to result in long-term impact on the phenotype that could become maladaptive under certain contexts later in life. This model has implications on our understanding of behavioural and mental health pathologies, as well as their diagnosis and therapeutics. [ABSTRACT FROM AUTHOR]
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- 2013
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10. DNA Methylation: A Mechanism for Embedding Early Life Experiences in the Genome.
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Szyf, Moshe and Bick, Johanna
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DNA methylation , *EPIGENETICS , *CHILD development , *EXPERIENCE , *GENOMICS , *EFFECT of environment on human beings - 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. [ABSTRACT FROM AUTHOR]
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- 2013
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11. Peripheral SLC6A4 DNA Methylation Is Associated with In Vivo Measures of Human Brain Serotonin Synthesis and Childhood Physical Aggression.
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Dongsha Wang, Szyf, Moshe, Benkelfat, Chawki, Provençal, Nadine, Turecki, Gustavo, Caramaschi, Doretta, Côté, Sylvana M., Vitaro, Frank, Tremblay, Richard E., and Booij, Linda
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DNA methylation , *SEROTONIN , *POSITRON emission tomography , *LEUCOCYTES , *T cells , *MONOCYTES , *BLOOD cells , *BINDING sites - Abstract
The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. [ABSTRACT FROM AUTHOR]
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- 2012
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12. The Implications of DNA Methylation for Toxicology: Toward Toxicomethylomics, the Toxicology of DNA Methylation.
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Szyf, Moshe
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METHYLATION , *GENETIC toxicology , *NUCLEOTIDE sequence , *CARCINOGENS , *GENE expression , *BIOLOGICAL assay , *MUTAGENESIS - Abstract
Identifying agents that have long-term deleterious impact on health but exhibit no immediate toxicity is of prime importance. It is well established that long-term toxicity of chemicals could be caused by their ability to generate changes in the DNA sequence through the process of mutagenesis. Several assays including the Ames test and its different modifications were developed to assess the mutagenic potential of chemicals (Ames, B. N., Durston, W. E., Yamasaki, E., and Lee, F. D. (1973a). Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl. Acad. Sci. U.S.A. 70, 2281–2285; Ames, B. N., Lee, F. D., and Durston, W. E. (1973b). An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc. Natl. Acad. Sci. U.S.A. 70, 782–786). These tests have also been employed for assessing the carcinogenic potential of compounds. However, the DNA molecule contains within its chemical structure two layers of information. The DNA sequence that bears the ancestral genetic information and the pattern of distribution of covalently bound methyl groups on cytosines in DNA. DNA methylation patterns are generated by an innate program during gestation but are attuned to the environment in utero and throughout life including physical and social exposures. DNA function and health could be stably altered by exposure to environmental agents without changing the sequence, just by changing the state of DNA methylation. Our current screening tests do not detect agents that have long-range impact on the phenotype without altering the genotype. The realization that long-range damage could be caused without changing the DNA sequence has important implications on the way we assess the safety of chemicals, drugs, and food and broadens the scope of definition of toxic agents. [ABSTRACT FROM AUTHOR]
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- 2011
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13. Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors.
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Chik, Flora and Szyf, Moshe
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METHYLTRANSFERASES , *ENZYME inhibitors , *TUMOR suppressor genes , *CANCER invasiveness , *CANCER cells , *CELL transformation , *METHYLATION , *DNA - Abstract
A hallmark of cancer is aberrant DNA methylation, consisting of global hypomethylation and regional hypermethylation of tumor suppressor genes. DNA methyltransferase inhibitors have been recognized as promising candidate anticancer drugs. Drug development has focused on DNA methylation inhibitors with the goal of activating tumor suppressor genes silenced by DNA methylation. 5-azacytidine (5-AC; Vidaza), a global DNA methyltransferase inhibitor, was Food and Drug Administration approved to treat myelodysplastic syndromes and is clinically tested for solid tumors. In this paper, it was demonstrated that 5′-aza-2′-deoxycytidine (5-azaCdR) activated both silenced tumor suppressor genes and pro-metastatic genes by demethylation, raising the concern that it would promote metastasis. 5-AzaCdR treatment increased the invasiveness of non-invasive breast cancer cell lines MCF-7 cells and ZR-75-1 and dramatically induced pro-metastatic genes; Urokinase plasminogen activator (uPA), matrix metalloproteinase 2 (MMP2), metastasis-associated gene (H-MTS1; S100A4) and C-X-C chemokine receptor 4 (CXCR4). The hypothesis that the blocking of cellular transformation activity of DNA methyltransferase inhibitor could be separated from the pro-metastatic activity was tested using short interfering RNA (siRNA) targeted to the different DNA methyltransferase (DNMT) genes. Although depletion of DNMT1 had the strongest effect on colony growth suppression in cellular transformation assays, it did not result in demethylation and activation of uPA, S100A4, MMP2 and CXCR4 in MCF-7 cells. Depletion of DNMT1 did not induce cellular invasion in MCF-7 and ZR-75-1 non-invasive breast cancer cell lines. These data have implications on the design of new DNA methyltransferase inhibitor and on the proper utilization of current inhibitors. [ABSTRACT FROM AUTHOR]
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- 2011
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14. The epigenetics of social adversity in early life: Implications for mental health outcomes
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McGowan, Patrick O. and Szyf, Moshe
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MENTAL health , *EPIGENESIS , *METHYLATION , *METHIONINE , *CHROMATIN , *NEUROLOGICAL disorders , *GENETIC polymorphisms - Abstract
Abstract: An organism''s behavioral and physiological and social milieu influence and are influenced by the epigenome, which is composed predominantly of chromatin and the covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the organism. In contrast to the genetic sequence, which is determined by inheritance and is virtually identical in all tissues, the epigenetic pattern varies from cell type to cell type and is potentially dynamic throughout life. It is postulated here that different environmental exposures, including early parental care, could impact epigenetic patterns, with important implications for mental health in humans. Because epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. Yet in contrast to genetic sequence differences, epigenetic alterations are potentially reversible. This review will discuss basic epigenetic mechanisms and how epigenetic processes early in life might play a role in defining inter-individual trajectories of human behavior. In this regard, we will examine evidence for the possibility that epigenetic mechanisms can contribute to later-onset neurological dysfunction and disease. [Copyright &y& Elsevier]
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- 2010
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15. The early life environment and the epigenome
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Szyf, Moshe
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HUMAN genome , *MOLECULAR genetics , *GENE expression , *PHENOTYPES , *GENETICS of disease susceptibility , *GENOTYPE-environment interaction , *METHYLTRANSFERASES , *HISTONES - Abstract
Abstract: Several lines of evidence point to the early origin of adult onset disease. A key question is: what are the mechanisms that mediate the effects of the early environment on our health? Another important question is: what is the impact of the environment during adulthood and how reversible are the effects of early life later in life? The genome is programmed by the epigenome, which is comprised of chromatin, a covalent modification of DNA by methylation and noncoding RNAs. The epigenome is sculpted during gestation, resulting in the diversity of gene expression programs in the distinct cell types of the organism. Recent data suggest that epigenetic programming of gene expression profiles is sensitive to the early-life environment and that both the chemical and social environment early in life could affect the manner by which the genome is programmed by the epigenome. We propose that epigenetic alterations early in life can have a life-long lasting impact on gene expression and thus on the phenotype, including susceptibility to disease. We will discuss data from animal models as well as recent data from human studies supporting the hypothesis that early life social-adversity leaves its marks on our epigenome and affects stress responsivity, health, and mental health later in life. [Copyright &y& Elsevier]
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- 2009
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16. Epigenetics, DNA Methylation, and Chromatin Modifying Drugs.
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Szyf, Moshe
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AUTOIMMUNE diseases , *IMMUNOLOGIC diseases , *DOSE-effect relationship in pharmacology , *DNA , *GENE expression , *NUCLEOTIDE sequence , *METHYLATION , *EPIGENESIS , *CHROMATIN - Abstract
Evidence is emerging that several diseases and behavioral pathologies result from defects in gene function. The best-studied example is cancer, but other diseases such as autoimmune disease, asthma, type 2 diabetes, metabolic disorders, and autism display aberrant gene expression. Gene function may be altered by either a change in the sequence of the DNA or a change in epigenetic programming of a gene in the absence of a sequence change. With epigenetic drugs, it is possible to reverse aberrant gene expression profiles associated with different disease states. Several epigenetic drugs targeting DNA methylation and histone deacetylation enxyrnes have been tested in clinical trials. Understanding the epigenetic machinery and the differential roles of its components in specific disease states is essential for developing targeted epigenetic therapy. [ABSTRACT FROM AUTHOR]
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- 2009
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17. DNA methylation-mediated nucleosome dynamics and oncogenic Ras signaling.
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Patra, Samir K. and Szyf, Moshe
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METHYLATION , *CHROMATIN , *GENETICS , *ONCOGENIC DNA viruses , *APOPTOSIS - Abstract
Cytosine methylation at the 5-carbon position is the only known stable base modification found in the mammalian genome. The organization and modification of chromatin is a key factor in programming gene expression patterns. Recent findings suggest that DNA methylation at the junction of transcription initiation and elongation plays a critical role in suppression of transcription. This effect is mechanistically mediated by the state of chromatin modification. DNA methylation attracts binding of methyl-CpG-binding domain proteins that trigger repression of transcription, whereas DNA demethylation facilitates transcription activation. Understanding the rules that guide differential gene expression, as well as transcription dynamics and transcript abundance, has proven to be a taxing problem for molecular biologists and oncologists alike. The use of novel molecular modeling methods is providing exciting insights into the challenging problem of how methylation mediates chromatin dynamics. New data implicate lipid rafts as the coordinators of signals emanating from the cell membrane and are converging on the mechanisms linking DNA methylation and chromatin dynamics. This review focuses on some of these recent advances and uses lipid-raft-facilitated Ras signaling as a paradigm for understanding DNA methylation, chromatin dynamics and apoptosis. [ABSTRACT FROM AUTHOR]
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- 2008
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18. Epigenetics, Behaviour, and Health.
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Szyf, Moshe and Meaney, Michael J.
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AUTOIMMUNE diseases , *SOCIAL status , *BEHAVIOR , *HEALTH , *ENVIRONMENTAL exposure , *CHILDREN'S health - Abstract
The long-term effects of behaviour and environmental exposures, particularly during childhood, on health outcomes are well documented. Particularly thought provoking is the notion that exposures to different social environments have a long-lasting impact on human physical health. However, the mechanisms mediating the effects of the environment are still unclear. In the last decade, the main focus of attention was the genome, and interindividual genetic polymorphisms were sought after as the principal basis for susceptibility to disease. However, it is becoming clear that recent dramatic increases in the incidence of certain human pathologies, such as asthma and type 2 diabetes, cannot be explained just on the basis of a genetic drift. It is therefore extremely important to unravel the molecular links between the "environmental" exposure, which is believed to be behind this emerging incidence in certain human pathologies, and the disease's molecular mechanisms. Although it is clear that most human pathologies involve long-term changes in gene function, these might be caused by mechanisms other than changes in the deoxyribonucleic acid (DNA) sequence. The genome is programmed by the epigenome, which is composed of chromatin and a covalent modification of DNA by methylation. It is postulated here that "epigenetic" mechanisms mediate the effects of behavioural and environmental exposures early in life, as well as lifelong environmental exposures and the susceptibility to disease later in life. In contrast to genetic sequence differences. epigenetic aberrations are potentially reversible, raising the hope for interventions that will be able to reverse deleterious epigenetic programming. [ABSTRACT FROM AUTHOR]
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- 2008
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19. Dynamic epigenetic states of ribosomal RNA promoters during the cell cycle.
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Brown, Shelley E. and Szyf, Moshe
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- 2008
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20. Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health
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Meaney, Michael J., Szyf, Moshe, and Seckl, Jonathan R.
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HYPOTHALAMIC-pituitary-adrenal axis , *LOW birth weight , *FETAL development , *MATERNAL nutrition , *CARDIOVASCULAR diseases , *METABOLIC disorders - Abstract
Environmental effects on the materno–foetal interaction determine birth outcomes that predict health over the lifespan. Thus, maternal undernutrition or stress associate with low birth weight, leading to an increased risk of metabolic and cardiovascular illness in the offspring. We argue that these effects are, in part, mediated by direct and indirect effects on the hypothalamic-pituitary-adrenal (HPA) axis such that (i) the effect of maternal adversity on foetal growth is mediated by adrenal glucocorticoids and (ii) environmental adversity alters maternal physiology and behaviour, which then programs HPA activity in the offspring. [Copyright &y& Elsevier]
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- 2007
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21. Maternal care, the epigenome and phenotypic differences in behavior
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Szyf, Moshe, Weaver, Ian, and Meaney, Michael
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HUMAN behavior , *GENOMES , *EPIGENESIS , *MOTHER-child relationship , *GENETICS - Abstract
Abstract: The genome is programmed by the epigenome, which is comprised of chromatin and a covalent modification of DNA by methylation. Epigenetic patterns are sculpted during development to shape the diversity of gene expression programs in the different cell types of the organism. The epigenome of the developing fetus is especially sensitive to maternal nutrition, and exposure to environmental toxins as well as psychological stress. It is postulated here that not only chemicals but also exposure of the young pup to social behavior, such as maternal care, could affect the epigenome. Since epigenetic programming defines the state of expression of genes, epigenetic differences could have the same consequences as genetic polymorphisms. We will propose here a mechanism linking maternal behavior and epigenetic programming and we will discuss the prospect that similar epigenetic variations generated during early life play a role in generating inter-individual differences in human behavior. We speculate that exposures to different environmental toxins, which affect the epigenetic machinery might alter long-established epigenetic programs in the brain. [Copyright &y& Elsevier]
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- 2007
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22. Epigenetic tête-à-tête: the bilateral relationship between chromatin modifications and DNA methylation.
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D'Alessio, Ana C. and Szyf, Moshe
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CHROMATIN , *PROTEINS , *DNA , *METHYLATION , *GENE expression , *EPIGENESIS , *CANCER cells - Abstract
The epigenome, which comprises chromatin, associated proteins, and the pattern of covalent modification of DNA by methylation, sets up and maintains gene expression programs. It was originally believed that DNA methylation was the dominant reaction in determining the chromatin structure. However, emerging data suggest that chromatin can affect DNA methylation in both directions, triggering either de novo DNA methylation or demethylation. These events are particularly important for the understanding of cellular transformation, which requires a coordinated change in gene expression profiles. While genetic alterations can explain some of the changes, the important role of epigenetic reprogramming is becoming more and more evident. Cancer cells exhibit a paradoxical coexistence of global loss of DNA methylation with regional hypermethylation. [ABSTRACT FROM AUTHOR]
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- 2006
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23. Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat
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Szyf, Moshe, Weaver, Ian C.G., Champagne, Francis A., Diorio, Josie, and Meaney, Michael J.
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NUCLEIC acids , *GENOTYPE-environment interaction , *GENE expression , *SEX hormones - Abstract
Abstract: Increased levels of pup licking/grooming and arched-back nursing by rat mothers over the first week of life alter the epigenome at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methylation pattern between the offspring of High and Low licking/grooming—arched-back mothers emerge over the first week of life, are reversed with cross-fostering, persist into adulthood and are associated with altered histone acetylation and transcription factor (NGFI-A) binding to the glucocorticoid receptor promoter. Central infusion of the adult offspring with the histone deacetylase inhibitor trichostatin A removes the previously defined epigenomic group differences in histone acetylation, DNA methylation, NGFI-A binding, glucocorticoid receptor expression, and hypothalamic-pituitary-adrenal responses to stress, thus suggesting a causal relation between the epigenomic state, glucocorticoid receptor expression and the effects of maternal care on stress responses in the offspring. These findings demonstrate that an epigenomic state of a gene can be established through a behavioral mode of programming and that in spite of the inherent stability of this epigenomic mark, it is dynamic and potentially reversible. [Copyright &y& Elsevier]
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- 2005
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24. Maternal care as a model for experience-dependent chromatin plasticity?
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Meaney, Michael J. and Szyf, Moshe
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CHILD care , *MOTHER-child relationship , *MATERNAL love , *CHILD rearing , *CHILD psychology , *CHILD development , *GENE expression - Abstract
It is widely acknowledged that the nature of the maternal care a child receives can have long-term repercussions, and that children raised in deprived environments can have severe cognitive and behavioural difficulties that last into adulthood. The mechanisms underlying these effects are not understood, but recent data from rodents provide insight into a potential molecular mechanism. Like humans, rodent maternal behaviour towards offspring can effect long-term changes in responses of the offspring to stress throughout the rest of their lives. Remarkably, these changes reflect permanently altered gene expression, so-called ‘environmental programming’, and its downstream effects on the hypothalamic–pituitary–adrenal axis. This review discusses the nature of this environmental programming – the mechanism by which it occurs in rats, its long-term implications, and opportunities for its reversal in rodents and ultimately in humans. [Copyright &y& Elsevier]
- Published
- 2005
- Full Text
- View/download PDF
25. DNA methylation and breast cancer
- Author
-
Szyf, Moshe, Pakneshan, Pouya, and Rabbani, Shafaat A.
- Subjects
- *
BREAST cancer , *ACETYLTRANSFERASES , *NUCLEOPROTEINS , *METHYLATION - Abstract
DNA methylation and chromatin structure patterns are tightly linked components of the epigenome, which regulate gene expression programming. Two contradictory changes in DNA methylation patterns are observed in breast cancer; regional hypermethylation of specific genes and global hypomethylation. It is proposed here that independent mechanisms are responsible for these alterations in DNA methylation patterns and that these alterations deregulate two different processes in breast cancer. Regional hypermethylation is brought about by specific regional changes in chromatin structure, whereas global demethylation is caused by a general increase in demethylation activity. Hypermethylation silences growth regulatory genes resulting in uncontrolled growth whereas hypomethylation leads to activation of genes required for metastasis. DNA methylation inhibitors activate silenced tumor suppressor genes resulting in arrest of tumor growth and are now being tested as candidate anticancer drugs. Demethylation inhibitors are proposed here to be potential novel candidate antimetastatic agents, which would bring about methylation and silencing of metastatic genes. Future therapeutic application of either methylation or demethylation inhibitors in cancer therapy would require understanding of the relative role of these processes in the evolution of cancer. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
26. DNA demethylation and cancer: therapeutic implications
- Author
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Szyf, Moshe, Pakneshan, Pouya, and Rabbani, Shafaat A.
- Subjects
- *
HISTONES , *BASIC proteins , *METASTASIS , *CANCER invasiveness - Abstract
The epigenome, which is comprised of chromatin and its associated proteins and the patterns of covalent modification of DNA by methylation, sets up and maintains gene expression programs. A hallmark of cancer is a paradoxical aberration of DNA methylation patterns, a global loss of DNA methylation, that coexists with regional hypermethylation of certain genes. The hypermethylation of tumor-suppressor genes has attracted significant attention recently and DNA methylation inhibitors are being tested as potential anticancer agents. However, emerging data suggests that hypomethylation plays a role in activating genes required for metastasis and invasion. It is proposed here that hypermethylation and hypomethylation in cancer are independent processes, which target different programs at different stages in tumorigenesis. Understanding the relative roles of hypomethylation and hypermethylation in cancer has clear implications on the therapeutic use of agents targeting the DNA methylation machinery, which are discussed in this review. [Copyright &y& Elsevier]
- Published
- 2004
- Full Text
- View/download PDF
27. Reversal of the Hypomethylation Status of Urokinase (uPA) Promoter Blocks Breast Cancer Growth and Metastasis.
- Author
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Pakneshan, Pouya, Szyf, Moshe, Farias-Eisner, Robin, and Rabbani, Shafaat A.
- Subjects
- *
UROKINASE , *BREAST cancer , *METASTASIS , *CANCER invasiveness , *GENES , *CARRIER proteins , *STEROID hormones , *TUMOR growth - Abstract
Metastasis is a leading cause of mortality and morbidity in cancer. Urokinase (uPA), only expressed by the highly invasive cancer cells, has been implicated in invasion, metastases, and angiogenesis of several malignancies including breast cancer. Because uPA expression is strongly correlated with its hypomethylated state, we utilized the uPA gene in the highly invasive MDA-231 human breast cancer cells as a model system to test the hypothesis that pharmacological reversal of the uPA promoter hypomethylation would result in its silencing and inhibition of metastasis. S-Adenosyl-L-methionine (AdoMet) has previously been shown to cause hypermethylation and inhibit demethylation. Treatmerit of MDA-231 cells with AdoMet, but not its unmethylated analogue S-adenosylhomocysteine, significantly inhibits uPA expression and tumor cell invasion in vitro and tumor growth and metastasis in vivo. The effects of AdoMet on uPA expression were reversed by the demethylating agent 5'-azacytidine, supporting the conclusion that AdoMet effects are caused by hypermethylation. Knockdown of the methyl-binding protein 2 also causes a significant inhibition of uPA expression in vitro and tumor growth and metastasis in vivo. These treatments did not have any effects on estrogen receptor expression, suggesting that inhibition of hypomethylation will not affect genes already silenced by hypermethylation. These data are consistent with the hypothesis that hypomethylation of critical genes like uPA plays a causal role in metastasis. Inhibition of hypomethylation can thus be used as a novel therapeutic approach to silence the pro-metastatic gene uPA and block breast cancer progression into the aggressive and metastatic stages of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
28. Targeting DNA methylation in cancer
- Author
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Szyf, Moshe
- Subjects
- *
METHYLATION , *DNA , *CANCER - Abstract
There is overwhelming evidence that DNA methylation patterns are altered in cancer. Methylation of CG-rich islands in regulatory regions of genes marks them for transcriptional silencing. Multiple genes, which confer selective advantage upon cancer cells such as tumor suppressors, adhesion molecules, inhibitors of angiogenesis and repair enzymes are silenced. In parallel, tumor cell genomes are globally less methylated than their normal counterparts. In contrast to regional hypermethylation, this loss of methylation in cancer cells occurs in sparsely distributed CG sequences. We now understand that DNA methylation machineries might include a number of DNA methyltransferases, proteins that direct DNA methyltransferases to specific promoters, chromatin modifying enzymes as well as demethylases. There is also data to suggest that pharmacological down regulation of some members of the DNA methylation machinery could inhibit cancer in vitro, in vivo and in clinical trials. Understanding which functions of DNA methylation machinery are critical for cancer is essential for the design of inhibitors of the DNA methylation machinery as anticancer agents. This review discusses the possible role of DNA methyltranferases and demethylases in tumorigenesis and the possible pharmacological and therapeutic implications of the DNA methylation machinery. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
29. Utilization of antisense oligonucleotides to study the role of 5-cytosine DNA methyltransferase in cellular transformation and oncogenesis
- Author
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Szyf, Moshe
- Subjects
- *
ANTISENSE nucleic acids , *OLIGONUCLEOTIDES - Abstract
A large body of data point toward 5-cytosine DNA methyltransferase 1 (DNMT1) as a critical component of oncogenic programs. The study of the role of DNMT1 in cancer has been hindered by the lack of specific inhibitors. A different approach to study the role of DNMT1 in cancer is to use sequence-specific antisense oligonucleotides against DNMT1 mRNA. This paper discusses methods used to identify sequence-specific antisense oligonucleotides and to assess their DNA methylation inhibitory properties. Antisense oligonucleotides are applied to determine whether DNMT1 plays a causal role in specific cancer models ex vivo as well as in vivo. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
30. Towards a pharmacology of DNA methylation.
- Author
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Szyf, Moshe
- Subjects
- *
METHYLTRANSFERASES , *DNA , *CANCER treatment , *REACTIVITY (Chemistry) , *METHYLATION - Abstract
Suggests that DNA methyltransferase 1 (DNMT1) is a multifunctional protein that has regulatory activities in addition to DNA methylation activity. Explanation on the reversibility of the DNA methylation pattern; Functional consequences of the coordinate regulation of DNMT1 and DNA replication; Therapeutic implications for the design of DNMT1 inhibitors for anti-cancer therapy.
- Published
- 2001
- Full Text
- View/download PDF
31. Lamarck revisited: epigenetic inheritance of ancestral odor fear conditioning.
- Author
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Szyf, Moshe
- Subjects
- *
ODOR control , *OLFACTORY receptors , *LABORATORY mice , *CHEMORECEPTORS - Abstract
The article offers information on a study that investigates the fear conditioning of odor in mice in Quebec. Researchers trained mice to fear odor acetophenone by mild shocks in the foot. Moreover, they found that when mice are conditioned to fear odor and the next generation of their offspring as well.
- Published
- 2014
- Full Text
- View/download PDF
32. The Dialogue Between Social Environments and the Genome.
- Author
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Szyf, Moshe
- Subjects
- *
GENES , *PUBLIC health , *SOCIAL sciences , *GENOMICS , *SOCIAL context - Abstract
The author reflects on the relationship between genomics and social environments and on research which investigated medical genetics. He suggests that the main challenge that scientists face is understanding how the human genetic landscape is shaped by the environment. He argues that social sciences and public health research must take the opportunity to integrate biological and chemical factors into their research and investigate the relationship between genomics and the environment.
- Published
- 2013
- Full Text
- View/download PDF
33. How do environments talk to genes?
- Author
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Szyf, Moshe
- Subjects
- *
GENOTYPE-environment interaction , *ALLELES , *DNA , *METHYL groups , *CHILDREN'S health - Abstract
The article focuses on gene-environment interaction. It states that a study conducted by researchers reveal that risk allele of FKBP5, which is a stress response regulator is demethylated in children who have been exposed to trauma. It mentions that DNA is marked by methyl groups during gestation in a process that is catalyzed by enzymes. It highlights that methyl groups may alter gene functions.
- Published
- 2013
- Full Text
- View/download PDF
34. Early life, the epigenome and human health.
- Author
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Szyf, Moshe
- Subjects
- *
HEALTH , *DNA , *METHYLATION , *CESAREAN section , *LEUCOCYTES , *DISEASES ,NEWBORN infant health - Abstract
In this article the author reflects upon the impact of early life environment on human health. He refers to a paper by T. Sclinzig and colleagues stating the presence of high levels of global DNA methylation in cord white cells of newborns delivered by caesarean section (CS) and discusses early life exposures that equal the methylation level of CS delivered babies as those with normal delivery. He analyzes various factors in early life environment that cause diseases in the later stage.
- Published
- 2009
- Full Text
- View/download PDF
35. Epigenetic signatures of social status in wild female spotted hyenas (Crocuta crocuta).
- Author
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Vullioud, Colin, Benhaiem, Sarah, Meneghini, Dorina, Szyf, Moshe, Shao, Yong, Hofer, Heribert, East, Marion L., Fickel, Jörns, and Weyrich, Alexandra
- Subjects
- *
SOCIAL status , *EPIGENETICS , *SOCIAL influence , *ION transport (Biology) , *FORAGING behavior - Abstract
In mammalian societies, dominance hierarchies translate into inequalities in health, reproductive performance and survival. DNA methylation is thought to mediate the effects of social status on gene expression and phenotypic outcomes, yet a study of social status-specific DNA methylation profiles in different age classes in a wild social mammal is missing. We tested for social status signatures in DNA methylation profiles in wild female spotted hyenas (Crocuta crocuta), cubs and adults, using non-invasively collected gut epithelium samples. In spotted hyena clans, female social status influences access to resources, foraging behavior, health, reproductive performance and survival. We identified 149 differentially methylated regions between 42 high- and low-ranking female spotted hyenas (cubs and adults). Differentially methylated genes were associated with energy conversion, immune function, glutamate receptor signalling and ion transport. Our results provide evidence that socio-environmental inequalities are reflected at the molecular level in cubs and adults in a wild social mammal. An epigenetic study on free-ranging spotted hyenas (Crocuta crocuta) suggests that genes are differentially methylated between high-ranking and low-ranking females (cubs and adults) which may reflect rank-specific differences in access to resources. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
36. The emerging field of pain epigenetics
- Author
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Stone, Laura S. and Szyf, Moshe
- Published
- 2013
- Full Text
- View/download PDF
37. A dynamic methylome; Implications of non-CG methylation/demethylation.
- Author
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Szyf, Moshe
- Published
- 2010
- Full Text
- View/download PDF
38. DNA methylation mediating the impact of exposure on behavior.
- Author
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Szyf, Moshe
- Subjects
- *
DNA methylation , *NEUROTOXICOLOGY , *MEDICAL research , *ANIMAL behavior , *NERVOUS system development - Published
- 2015
- Full Text
- View/download PDF
39. Serotonin transporter gene promoter methylation in peripheral cells in healthy adults: Neural correlates and tissue specificity.
- Author
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Ismaylova, Elmira, Di Sante, Jessica, Szyf, Moshe, Nemoda, Zsofia, Yu, Wei-Jo, Pomares, Florence B., Turecki, Gustavo, Gobbi, Gabriella, Vitaro, Frank, Tremblay, Richard E., and Booij, Linda
- Subjects
- *
SEROTONIN transporters , *PROMOTERS (Genetics) , *DNA methylation , *EPIGENETICS , *MAGNETIC resonance imaging of the brain , *HEALTH of adults - Abstract
Early adversity can influence gene expression via epigenetic mechanisms, including DNA methylation. Peripheral tissues are essential in psychiatric epigenetics, as methylation generally cannot be assessed in the living human brain. Several magnetic resonance imaging (MRI) studies show associations of peripheral serotonin transporter gene (SLC6A4) methylation with function and/or structure of frontal-limbic circuits and brain's resting-state. Commonly used samples are derived from blood, saliva or buccal cells. However, little is known regarding which peripheral tissue is most strongly associated with human brain processes. The aim of the current study was to compare the extent of the association between peripheral SLC6A4 promoter methylation and frontal-limbic function, structure and resting-state in healthy individuals across peripheral tissues. Forty healthy prospectively-followed adults underwent anatomical, resting-state and functional MRI. Saliva-, blood- and buccal-derived DNA methylation was assessed by pyrosequencing. Blood-derived SLC6A4 methylation was positively associated with superior frontal gray matter (GM) volume and with right lateral parietal area (RLP)-frontal pole regional resting-state functional connectivity (rsFC). Saliva-derived SLC6A4 methylation was positively associated with superior frontal GM volume. Buccal-derived SLC6A4 methylation was positively associated with superior and inferior frontal and anterior cingulate cortical (ACC) GM volumes, and with RLP-ACC, frontal pole and medial prefrontal regional rsFC. Current results confirmed the relevance of peripheral methylation for frontal-limbic processes in humans. Buccal cells may be the most sensitive cell type when studying SLC6A4 promoter methylation and its associated risk for neural vulnerability and resilience for psychopathologies in which serotonin is implicated. These data should be further validated in clinical populations. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
40. S4-1: System and genome wide adaptation of the epigenome to gestational stress: Supported in part by March of Dimes Foundation Grant No. 4-FY13-534.
- Author
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Szyf, Moshe
- Published
- 2013
- Full Text
- View/download PDF
41. DNA methylation in people with anorexia nervosa: Epigenome-wide patterns in actively ill, long-term remitted, and healthy-eater women.
- Author
-
Steiger, Howard, Booij, Linda, Thaler, Lea, St-Hilaire, Annie, Israël, Mimi, Casey, Kevin F., Oliverio, Stephanie, Crescenzi, Olivia, Lee, Viveca, Turecki, Gustavo, Joober, Ridha, Szyf, Moshe, and Breton, Édith
- Subjects
- *
DNA methylation , *ANOREXIA nervosa , *METHYLATION , *EATING disorders , *GENE expression , *GENE mapping - Abstract
Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion. We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED. Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups (Q < 0.01). Probes tended to map onto genes relevant to psychiatric, metabolic and immune functions. Notably, several of the genes identified here as being differentially methylated in people with AN (e.g. SYNJ2, PRKAG2, STAT3, CSGALNACT1, NEGR1, NR1H3) have figured in previous studies on AN. Effects also associated illness chronicity and lower BMI with more pronounced DNA methylation alterations, and remission of AN with normalisation of DNA methylation. Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
42. Birth weight discordance, DNA methylation, and cortical morphology of adolescent monozygotic twins.
- Author
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Casey, Kevin F., Levesque, Melissa L., Szyf, Moshe, Ismaylova, Elmira, Verner, Marie ‐ Pier, Suderman, Matthew, Vitaro, Frank, Brendgen, Mara, Dionne, Ginette, Boivin, Michel, Tremblay, Richard E., and Booij, Linda
- Abstract
Background Several studies have shown that the in utero environment, which can be indexed by birth weight (BW), is associated with cortical morphology in adolescence and adulthood. Work in monozygotic (MZ) twins suggests that this association is driven by non-shared environmental factors. This correlation could be the result of in utero impacts on DNA methylation. The aim of the present study with MZ twins is to replicate the association between discordance in BW and brain morphology and test whether discordance in DNA methylation mediates this relationship. Methods One hundred and four adolescent MZ twins (52 pairs, of which 42% were male pairs) who have been followed regularly since birth underwent T1 weighted structural MRI, and epigenome-wide assessment of DNA methylation from saliva at age 15. Results Co-twins had very similar measures of DNA methylation and cortical morphology. Higher BW members of a twin pair had increased total cortical surface area, and decreased cortical thickness compared to their lower BW sibling. BW Discordance was positively associated with both cortical surface area and cortical volume discordance. Genes involved in neurodevelopment were tentatively identified as mediators of both the BW - cortical volume, and BW- cortical surface area relationships. Conclusions The association between BW and cortical morphology in adolescence appears to be attributable to in utero environmental effects, and DNA methylation may play a role in mediating this relationship. Hum Brain Mapp 38:2037-2050, 2017. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
43. Co-Targeting Luminal B Breast Cancer with S-Adenosylmethionine and Immune Checkpoint Inhibitor Reduces Primary Tumor Growth and Progression, and Metastasis to Lungs and Bone.
- Author
-
Mehdi, Ali, Attias, Mikhael, Arakelian, Ani, Piccirillo, Ciriaco A., Szyf, Moshe, and Rabbani, Shafaat A.
- Subjects
- *
DISEASE progression , *IN vitro studies , *IMMUNE checkpoint inhibitors , *IN vivo studies , *ANIMAL experimentation , *LUNG tumors , *TREATMENT effectiveness , *COMPARATIVE studies , *BONE metastasis , *RESEARCH funding , *CELL proliferation , *GENE expression profiling , *TUMORS , *BREAST tumors , *ADENOSYLMETHIONINE , *MICE , *PHARMACODYNAMICS - Abstract
Simple Summary: Breast cancer (BCa) is a devastating disease, which has a high prevalence and mortality in women. BCa metastasis is a major cause of mortality, and bone metastasis accounts for the majority of BCa-associated deaths. The luminal B subtype of BCa is immunogenically low and has the highest propensity to form bone metastasis compared to other BCa subtypes. Recent efforts have targeted BCa with immune checkpoint inhibitor (CPI) therapy. Although some clinical success in other BCa subtypes, luminal BCas had limited success. This has led to combining immune-stimulating therapies with CPIs to enhance the effectiveness of CPI therapy. We have demonstrated that a natural methyl donor, S-adenosylmethionine (SAM), has significant anti-cancer effects in various cancer models including all subtypes of BCa. Here, we show that SAM in combination with anti-PD-1 antibody has an enhanced anti-cancer efficacy compared to SAM, anti-PD-1 antibody, and control. The combination significantly reduced primary tumor growth and metastasis to lungs and bone. Hence, combining SAM with CPI has the potential to treat luminal B BCa. Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, it has had limited success in luminal subtypes of BCa. Accordingly, recent efforts have focused on combination therapy with CPI, including epigenetic modulators, to increase response rates of CPI in luminal BCa. We have previously shown that S-adenosylmethionine (SAM), the ubiquitous methyl donor, has strong anti-cancer effects in various cancers, including all subtypes of BCa. In the current study, we took a novel approach and examined the effect of CPI alone and in combination with SAM on tumor growth and metastasis in a syngeneic mouse model of luminal B BCa. We showed that SAM decreases cell proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines (Eo771, R221A) in vitro. In in vivo studies, in Eo771 tumor-bearing mice, either SAM or anti-PD-1 antibody treatment alone significantly reduced tumor growth and progression, while the SAM+anti-PD-1 combination treatment had the highest anti-cancer efficacy of all groups. The SAM+anti-PD-1 combination reduced the percentage of animals with lung metastasis, as well as total metastatic lesion area, compared to control. Additionally, the SAM+anti-PD-1 combination significantly reduced the skeletal lesion area and protected tibial integrity to a greater extent than the monotherapies in an Eo771 bone metastasis model. Transcriptome analysis of Eo771 primary tumors revealed significant downregulation of pro-metastatic genes, including Matrix metalloproteinases (MMPs) and related pathways. On the other hand, CD8+ T cell infiltration, CD8+ T cell cytotoxicity (elevated granzymes), and immunostimulatory genes and pathways were significantly upregulated by the combination treatment. The results presented point to a combination of SAM with CPI as a possible treatment for luminal B BCa that should be tested in clinical studies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
44. The implication of DNA methylation on toxicology: Towards toxicomethylomics; the toxicology of DNA methylation
- Author
-
Szyf, Moshe
- Published
- 2011
- Full Text
- View/download PDF
45. Behavior and Epigenetics: Long-term Plasticity of the Epigenome?
- Author
-
Szyf, Moshe
- Subjects
- *
BEHAVIOR , *DNA , *ECOLOGY , *HUMAN genome , *METABOLISM - Abstract
The article focuses on studies from rat, rhesus monkeys and human which delineate the signature of early life adversity on the epigenome as well as how the dynamic epigenome plays a critical role in cancer. The notion that there is a well-defined epigenomic response to different environmental cues in difference from the random-chance appearance of single nucleotide polymorphisms has been supported in the study. It also notes that epigenetics is potentially reversible by dietary, therapeutic and social interventions in contrast to genetics.
- Published
- 2010
- Full Text
- View/download PDF
46. Epigenetic Programming of the rRNA Promoter by MBD3.
- Author
-
Brown, Shelley E. and Szyf, Moshe
- Subjects
- *
RNA , *HUMAN genome , *GENE silencing , *EPIGENESIS , *CARRIER proteins , *RNA polymerases , *METHYLATION , *PROMOTERS (Genetics) - Abstract
Within the human genome there are hundreds of copies of the rRNA gene, but only a fraction of these genes are active. Silencing through epigenetics has been extensively studied; however, it is essential to understand how active rRNA genes are maintained. Here, we propose a role for the methyl-CpG binding domain protein MBD3 in epigenetically maintaining active rRNA promoters. We show that MBD3 is localized to the nucleolus, colocalizes with upstream binding factor, and binds to unmethylated rRNA promoters. Knockdown of MBD3 by small interfering RNA results in increased methylation of the rRNA promoter coupled with a decrease in RNA polymerase I binding and pre-rRNA transcription. Conversely, overexpression of MBD3 results in decreased methylation of the rRNA promoter. Additionally, overexpression of MBD3 induces demethylation of nonreplicating plasmids containing the rRNA promoter. We demonstrate that this demethylation occurs following the overexpression of MBD3 and its increased interaction with the methylated rRNA promoter. This is the first demonstration that MBD3 is involved in inducing and maintaining the demethylated state of a specific promoter. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
47. FROM MATERNAL CARE TO GENE EXPRESSION: DNA METHYLATION AND THE MATERNAL PROGRAMMING OF STRESS RESPONSES.
- Author
-
Weaver, Ian C. G., Szyf, Moshe, and Meaney, Michael J.
- Subjects
- *
HYPOTHALAMIC-pituitary-adrenal axis , *LABORATORY rats , *PARENTAL behavior in animals , *GLUCOCORTICOIDS - Abstract
Discusses the influences of maternal care of pups to the development of hypothalamic-pituitary-adrenal responses to stress in the rat. Show of an increased frequency of pup licking/grooming by the adult offspring of mothers; Mediation of the effects by changes in hippocampal glucocorticoid receptor expression; Association of the effects of maternal care on GR expression and transcription fator NGF1-A expression.
- Published
- 2002
- Full Text
- View/download PDF
48. The role of DNA demethylation in liver to pancreas transdifferentiation.
- Author
-
Har-Zahav, Adi, Lixandru, Daniela, Cheishvili, David, Matei, Ioan Valentin, Florea, Ioana Raluca, Aspritoiu, Veronica Madalina, Blus-Kadosh, Inna, Meivar-Levy, Irit, Serban, Andreea Madalina, Popescu, Irinel, Szyf, Moshe, Ferber, Sarah, and Dima, Simona Olimpia
- Subjects
- *
DNA demethylation , *PANCREAS , *LIVER cells , *DNA methylation , *LIVER , *TRANSCRIPTION factors , *DNA methyltransferases - Abstract
Background: Insulin producing cells generated by liver cell transdifferentiation, could serve as an attractive source for regenerative medicine. The present study assesses the relationship between DNA methylation pTFs induced liver to pancreas transdifferentiation. Results: The transdifferentiation process is associated with DNA demethylation, mainly at gene regulatory sites, and with increased expression of these genes. Active inhibition of DNA methylation promotes the pancreatic transcription factor-induced transdifferentiation process, supporting a causal role for DNA demethylation in this process. Conclusions: Transdifferentiation is associated with global DNA hypomethylation, and with increased expression of specific demethylated genes. A combination of epigenetic modulators may be used to increase chromatin accessibility of the pancreatic transcription factors, thus promoting the efficiency of the developmental process. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
49. Impact of Early Environment on Children's Mental Health: Lessons From DNA Methylation Studies With Monozygotic Twins.
- Author
-
Chiarella, Julian, Tremblay, Richard E., Szyf, Moshe, Provençal, Nadine, Booij, Linda, Craig, Jeff, Saffery, Richard, and Provençal, Nadine
- Subjects
- *
CHILD psychology , *MENTAL health , *DNA methylation , *DISEASES in twins , *EPIGENETICS , *PATHOLOGICAL psychology , *DNA copy number variations , *BRAIN physiology , *BEHAVIOR , *EPIDEMIOLOGICAL research , *FORECASTING , *GENES , *MEDICAL research , *MENTAL illness , *RESEARCH funding , *TWINS , *PHENOTYPES - Abstract
Over the past decade, epigenetic analyses have made important contributions to our understanding of healthy development and a wide variety of adverse conditions such as cancer and psychopathology. There is increasing evidence that DNA methylation is a mechanism by which environmental factors influence gene transcription and, ultimately, phenotype. However, differentiating the effects of the environment from those of genetics on DNA methylation profiles remains a significant challenge. Monozygotic (MZ) twin study designs are unique in their ability to control for genetic differences because each pair of MZ twins shares essentially the same genetic sequence with the exception of a small number of de novo mutations and copy number variations. Thus, differences within twin pairs in gene expression and phenotype, including behavior, can be attributed in the majority of cases to environmental effects rather than genetic influence. In this article, we review the literature showing how MZ twin designs can be used to study basic epigenetic principles, contributing to understanding the role of early in utero and postnatal environmental factors on the development of psychopathology. We also highlight the importance of initiating longitudinal and experimental studies with MZ twins during pregnancy. This approach is especially important to identify: (1) critical time periods during which the early environment can impact brain and mental health development, and (2) the specific mechanisms through which early environmental effects may be mediated. These studies may inform the optimum timing and design for early preventive interventions aimed at reducing risk for psychopathology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
50. Corrigendum to "Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo" [Neoplasia 10/3 (2008) 266-278].
- Author
-
Ateeq, Bushra, Unterberger, Alexander, Szyf, Moshe, and ARabbani, Shafaat
- Subjects
- *
DNA methylation , *TUMORS , *GENES , *DEMETHYLATION - Published
- 2022
- Full Text
- View/download PDF
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