Spl elements protect a CpG island from de novo methylation

Brandeis, Michael; Frank, Dale; Keshet, Ilana; Siegfried, Zahava; Mendelsohn, Monica; Nemes, Adriana; Temper, Violeta; Razin, Aharon; Cedar, Howard

doi:10.1038/371435a0

Cited by 672 publications

(490 citation statements)

References 25 publications

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“…Several studies in the literature point to a potential role for SP1 binding sites in maintaining the CpG island in an unmethylated and transcriptionally active state (Gra et al, 1997;Clark et al, 1997;Macleod et al, 1994;Brandeis et al, 1994). In contrast to many other transcription factors, SP1 has until recently been shown to bind to its recognition sequence regardless of its methylation status.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the SP1 transcription factor is critical for both transcription (Macleod et al, 1994;Brandeis et al, 1994;Holler et al, 1988;Worrad and Schultz, 1997) as well as for the maintenance of methylation-free status within CpGrich regions (Clark et al, 1997;Gra et al, 1997). Analysis of the NF1 promoter using TFSEARCH localized several putative SP1 motifs.…”

Section: Methylation and Sp1 Bindingmentioning

confidence: 97%

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Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

et al. 1999

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Tumour suppressor genes and growth regulatory genes are frequent targets for methylation defects that can result in aberrant expression and mutagenesis. We have established a methylation map of the promoter region of the neuro®bromatosis (NF1) gene and demonstrated functional sensitivity for methylation at speci®c sites for the SP1 and CRE binding (CREB) proteins in the NF1 regulatory region. We evaluated the methylation status of CpG dinucleotides within ®ve promoter subregions in the human and mouse homologues of the neuro®bromatosis (NF1) genes. Three 5' subregions were found to be consistently methylated in all the tissues analysed. In contrast, DNA methylation was absent in the vicinity of the transcription start site bounded by SP1 recognition sequences. Gelshift assays showed that methylation speci®cally inhibits the CREB transcription factor from binding to its recognition site at the NF1 transcription start site. Furthermore, SP1 elements within the NF1 promoter are methylation sensitive, particularly when methylation is present on the antisense strand. We propose that for NF1 as with several other tumour suppressor genes, CpG methylation occurs in a complex, site-speci®c manner with the maintenance of a methylation-free promoter region bounded by SP1 binding sites that allow an accessible promoter to be retained. When these SP1 boundaries are breached, methylation can sweep in, rendering the promoter inaccessible for speci®c methylation-sensitive transcription factors and leading to a loss of functional integrity of the methylation-free CpG island.

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Section: Discussionmentioning

confidence: 99%

Section: Methylation and Sp1 Bindingmentioning

confidence: 97%

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

et al. 1999

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“…HDAC inhibitors act in synergy with 5-aza-2-deoxycytidine to demethylate DNA and increase transcriptional activation. Overexpression of the transcription factor SP-1 associates with both an increase and a decrease in the level of cytosine methylation, depending upon the pre-existing level of methylation [78,79]. DNA methylation, although stable, is altered in response to the opening of chromatin structure and transcriptional activation.…”

Section: The Epigenome: Chromatin Structure and Dna Methylationmentioning

confidence: 99%

Environmental regulation of the neural epigenome

et al. 2011

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a b s t r a c tParental effects are a major source of phenotypic plasticity. Moreover, there is evidence from studies with a wide range of species that the relevant parental signals are influenced by the quality of the parental environment. The link between the quality of the environment and the nature of the parental signal is consistent with the idea that parental effects, whether direct or indirect, might serve to influence the phenotype of the offspring in a manner that is consistent with the prevailing environmental demands. In this review we explore recent studies from the field of 'environmental epigenetics' that suggest that (1) DNA methylation states are far more variable than once thought and that, at least within specific regions of the genome, there is evidence for both demethylation and remethylation in post-mitotic cells and (2) that such remodeling of DNA methylation can occur in response to environmentally-driven, intracellular signaling pathways. Thus, studies of variation in mother-offspring interactions in rodents suggest that parental signals operate during pre-and/ or post-natal life to influence the DNA methylation state at specific regions of the genome leading to sustained changes in gene expression and function. We suggest that DNA methylation is a candidate mechanism for parental effects on phenotypic variation.

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“…Interestingly, when a methylated island is inserted into ES cells, it undergoes complete demethylation (Frank et al 1991;Brandeis et al 1994). This experiment strongly suggests that the generation of the bimodal methylation pattern at the time of implantation is actually carried out by two separate activities, generalized de novo modification, accompanied by demethylation of CpG island sequences.…”

Section: Generation Of the Methylation Patternmentioning

confidence: 89%

The role of DNA demethylation during development

Weiss

Cedar

1997

Genes to Cells

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The somatic genomic methylation pattern which plays a role in the suppression of basal gene activity is established anew in each generation through developmentally regulated de novo and demethylation steps. Demethylation appears to be carried out by a nucleotide exchange reaction which may involve RNA molecules, and is directed to specific loci in the genome through interactions between cis acting elements and trans acting factors.

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Spl elements protect a CpG island from de novo methylation

Cited by 672 publications

References 25 publications

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors

Environmental regulation of the neural epigenome

The role of DNA demethylation during development

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