Directing DNA Methylation to Inhibit Gene Expression

Hoffman, Andrew R.; Hu, Ji Fan

doi:10.1007/s10571-006-9057-5

Cited by 45 publications

(31 citation statements)

References 38 publications

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“…We focused on Region_M1 because CpG sequences near the TSS were previously shown to be the best targets for gene silencing [23] and because the association between gli2 hypermethylation and an increased risk of spina bifida was identified in Region_M1 not Region_M2. Our results show that methylation levels of gli2 were negatively correlated with its transcription level, suggesting an essential role for methylation in regulating gli2 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

et al. 2015

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GLI2 is a key mediator of the sonic hedgehog (Shh) signaling pathway and plays an important role in neural tube development during vertebrate embryogenesis; however, the role of gli2 in human folate-related neural tube defects remains unclear. In this study, we compared methylation status and polymorphisms of gli2 between spina bifida patients and a control group to explore the underlying mechanisms related to folate deficiency in spina bifida. No single nucleotide polymorphism was found to be significantly different between the two groups, although gli2 methylation levels were significantly increased in spina bifida samples, accompanied by aberrant GLI2 expression. Moreover, a prominent negative correlation was found between the folate level in brain tissue and the gli2 methylation status (r = -0.41, P = 0.014), and gli2 hypermethylation increased the risk of spina bifida with an odds ratio of 12.45 (95 % confidence interval: 2.71-57.22, P = 0.001). In addition, we established a cell model to illustrate the effect of gli2 expression and the accessibility of chromatin affected by methylation. High gli2 and gli1 mRNA expression was detected in 5-Aza-treated cells, while gli2 hypermethylation resulted in chromatin inaccessibility and a reduced association with nuclear proteins containing transcriptional factors. More meaningful to the pathway, the effect gene of the Shh pathway, gli1, was found to have a reduced level of expression along with a decreased expression of gli2 in our cell model. Aberrant high methylation resulted in the low expression of gli2 in spina bifida, which was affected by the change in chromatin status and the capacity of transcription factor binding.

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Section: Discussionmentioning

confidence: 99%

Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

et al. 2015

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“…DNA methylation patterns are largely established during embryogenesis and early postnatal life, and are crucial for various cellular processes including long-term gene silencing [27,28], proper development [29], X chromosome inactivation [30] and genomic imprinting [31,32]. Reprogramming is generally defined as the process reverting the nucleus of a differentiated cell to a pluripotent or totipotent state.…”

Section: Dna Methylation-demethylation Patternsmentioning

confidence: 99%

Epigenetic Programming and Risk: The Birthplace of Cardiovascular Disease?

Vinci

Polvani

Pesce

2012

Stem Cell Rev and Rep

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Epigenetics, through control of gene expression circuitries, plays important roles in various physiological processes such as stem cell differentiation and self renewal. This occurs during embryonic development, in different tissues, and in response to environmental stimuli. The language of epigenetic program is based on specific covalent modifications of DNA and chromatin. Thus, in addition to the individual identity, encoded by sequence of the four bases of the DNA, there is a cell type identity characterized by its positioning in the epigenetic "landscape". Aberrant changes in epigenetic marks induced by environmental cues may contribute to the development of abnormal phenotypes associated with different human diseases such as cancer, neurological disorders and inflammation. Most of the epigenetic studies have focused on embryonic development and cancer biology, while little has been done to explore the role of epigenetic mechanisms in the pathogenesis of cardiovascular disease. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodeling and histone modifications play key roles in the pathogenesis of cardiovascular disease through (re)programming of cardiovascular (stem) cells commitment, identity and function.

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“…The methyl groups create target sites for methylbinding proteins which induce transcriptional repression by recruiting co-repressors such as histone deacetylases [24]. So, DNA methylation largely contributes to long-term gene silencing [25,26], and as such it is essential for development [27][28][29][30], X chromosome inactivation [31], and genomic imprinting [32][33][34][35]. The relationship between DNA methylation and gene expression is complex [36], and recent evidence based on genome-wide CpG methylation profiling highlights promoter CpG content as a component of this complexity [37].…”

Section: Dna Methylation and Gene Expressionmentioning

confidence: 99%

Epigenetic Basis for the Differentiation Potential of Mesenchymal and Embryonic Stem Cells

Collas

Noer

Sørensen

2008

Transfus Med Hemother

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Stem cells have the ability to self-renew, and give rise to one or more differentiated cell types. Embryonic stem cells can differentiate into all cell types of the body and have unlimited self-renewal capacity. Somatic stem cells are found in many adult tissues. They have an extensive but finite lifespan and can differentiate into a more restricted range of cell types. Increasing evidence indicates that the multilineage differentiation ability of stem cells is defined by the potential for expression of developmentally regulated transcription factors and of lineage specification genes. Gene expression, or as emphasized here, the potential for gene expression, is largely controlled by epigenetic modifications of DNA (DNA methylation) and chromatin (such as post-translational histone modifications) in the regulatory regions of specific genes. Epigenetic modifications can also influence the timing of DNA replication. We highlight here how mechanisms by which genes are poised for transcription in undifferentiated stem cells are being uncovered through the mapping of DNA methylation profiles on differentiation-regulated promoters and at the genome-wide level, histone modifications, and transcription factor binding. Epigenetic marks on developmentally regulated and lineage specification genes in stem cells seem to define a state of pluripotency.

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Directing DNA Methylation to Inhibit Gene Expression

Cited by 45 publications

References 38 publications

Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

Sonic Hedgehog Signaling Affected by Promoter Hypermethylation Induces Aberrant Gli2 Expression in Spina Bifida

Epigenetic Programming and Risk: The Birthplace of Cardiovascular Disease?

Epigenetic Basis for the Differentiation Potential of Mesenchymal and Embryonic Stem Cells

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