Induction of myogenic differentiation by an expression vector encoding the DNA methyltransferase cDNA sequence in the antisense orientation.

Szyf, Moshe; Rouleau, J.; Théberge, Johanne; Bozovic, V

doi:10.1016/s0021-9258(18)42351-4

Cited by 57 publications

(6 citation statements)

References 33 publications

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“…Cellular differentiation of pluripotent cells involves extensive changes in DNA methylation . Either the DNA methylation inhibitor 5-azaC (Jones and Taylor, 1980) or depletion of DNMT by antisense knockdown triggers cellular differentiation (Szyf et al, 1992). As expected, recent high-throughput sequencing of the DNA methylome confirms that stem cell differentiation is associated with extensive changes in methylation of differentially methylated regions (Lister et al, 2009).…”

Section: Dna Methylation Patterns and The Impact Of Toxic Agents During Embryogenesissupporting

confidence: 63%

The Implications of DNA Methylation for Toxicology: Toward Toxicomethylomics, the Toxicology of DNA Methylation

Szyf¹

2011

Toxicological Sciences

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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.

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Section: Dna Methylation Patterns and The Impact Of Toxic Agents During Embryogenesissupporting

confidence: 63%

The Implications of DNA Methylation for Toxicology: Toward Toxicomethylomics, the Toxicology of DNA Methylation

Szyf¹

2011

Toxicological Sciences

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“…20 Second, treating cells with DNA methylation inhibitor 5-azacytidine activates gene expression. 21 Third, knockdown of DNMT1 in cells 22 or genetic knockout in mice results in changes in gene expression. 10 There is still no evidence that demethylation of a specific set of sites can induce gene expression.…”

Section: Dna Methylation Plays a Causal Role In Regulation Of Gene Expressionmentioning

confidence: 99%

The epigenetics of perinatal stress

Szyf

2019

Dialogues in Clinical Neuroscience

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Early life adversity is associated with long-term effects on physical and mental health later in life, but the mechanisms are yet unclear. Epigenetic mechanisms program cell-type-specific gene expression during development, enabling one genome to be programmed in many ways, resulting in diverse stable profiles of gene expression in different cells and organs in the body. 􀀧NA methylation, an enzymatic covalent modification of 􀀧NA, has been one of the principal epigenetic mechanisms investigated. Emerging evidence is consistent with the idea that epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Whereas there is evidence supporting this hypothesis in animal studies, human studies have been less conclusive. A major problem is the fact that the brain is inaccessible to epigenetic studies in humans and the relevance of DNA methylation in peripheral tissues to behavioral phenotypes has been questioned. In addition, human studies are usually confounded with genetic and environmental heterogeneity and it is very difficult to derive causality. The idea that epigenetic mechanisms mediate the life-long effects of perinatal adversity has attractive potential implications for early detection, prevention, and intervention in mental health disorders will be discussed.

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“…In reality, DNA methylation is implicated in muscle development and differentiation (Carrio & Suelves, ), and several methylome studies have shown chronological alterations in DNA methylation during myogenic differentiation from cultured myoblasts to a myotube (Tsumagari et al, ). Furthermore, many genes with muscle‐specific expression, including MYOD (Brunk, Goldhamer, & Emerson, ), MYOG (Fuso et al, ), α‐SMA (Hu, Gharaee‐Kermani, Wu, & Phan, ), and SIX1 (Wu et al, ), are transcriptionally regulated by de novo methylation and demethylation; for example, the gene expression changes after treatment with 5‐azacytidine (Montesano, Luzi, Senesi, & Terruzzi, ) or DNMT1 antisense cDNA (Szyf, Rouleau, Theberge, & Bozovic, ).…”

Section: Introductionmentioning

confidence: 99%

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

2019

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Changes in DNA methylation influence the aging process and contribute to aging phenotypes, but few studies have been conducted on DNA methylation changes in conjunction with skeletal muscle aging. We explored the DNA methylation changes in a variety of retroelement families throughout aging (at 2, 20, and 28 months of age) in murine skeletal muscles by methyl‐binding domain sequencing (MBD‐seq). The two following contrasting patterns were observed among the members of each repeat family in superaged mice: (a) hypermethylation in weakly methylated retroelement copies and (b) hypomethylation in copies with relatively stronger methylation levels, representing a pattern of “regression toward the mean” within a single retroelement family. Interestingly, these patterns depended on the sizes of the copies. While the majority of the elements showed a slight increase in methylation, the larger copies (>5 kb) displayed evident demethylation. All these changes were not observed in T cells. RNA sequencing revealed a global derepression of retroelements during the late phase of aging (between 20 and 28 months of age), which temporally coincided with retroelement demethylation. Following this methylation drift trend of “regression toward the mean,” aging tended to progressively lose the preexisting methylation differences and local patterns in the genomic regions that had been elaborately established during the early period of development.

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Induction of myogenic differentiation by an expression vector encoding the DNA methyltransferase cDNA sequence in the antisense orientation.

Cited by 57 publications

References 33 publications

The Implications of DNA Methylation for Toxicology: Toward Toxicomethylomics, the Toxicology of DNA Methylation

The Implications of DNA Methylation for Toxicology: Toward Toxicomethylomics, the Toxicology of DNA Methylation

The epigenetics of perinatal stress

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

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