Differential Sensitivity of Zinc Finger Transcription Factors MTF-1, Sp1 and Krox-20 to CpG Methylation of Their Binding Sites

Radtke, Freddy; Hug, Martin; Georgiev, Oleg; Matsuo, Koichi; Schaffner, Walter

doi:10.1515/bchm3.1996.377.1.47

Cited by 34 publications

(19 citation statements)

References 48 publications

(61 reference statements)

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“…Loss of expression was correlated with methylation of the respective promoter region, mainly at CpG and CpNpG sites, and inhibition of methylation restored the original expression pattern, suggesting methylation as a cause for promoter inactivation in the vascular tissue. Direct interference of a methyl group with protein binding has been described for several transcription factors in animals (38,(44)(45)(46)(47)(48)(49)(50)(51) and plants (39,52,53). Interference can be absolute or depend on the degree of methylation or the context of a binding site (45,46,50,54,55), and it can result in methylation-dependent silencing (56).…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific silencing of a transgene in rice

Klöti

Potrykus

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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In a transgenic rice line, a ␤-glucuronidase reporter gene under the control of the rice tungro bacilliform virus promoter became gradually methylated, and gene activity was lost concomitantly. Methylation was observed only in the homozygous offspring and was initially restricted to the promoter region and accompanied by loss of expression in the vascular bundle tissue only. This expression pattern was similar to that of a promoter with a deletion of a vascular bundle expression element. The gene activity could be reestablished by treatment with 5-azacytidine. Methylation per se did not inhibit the binding to the promoter region of protein factors which also bound to the unmethylated sequence. Instead, promoter methylation enabled the alternative binding of a protein with specificity for sequence and methylation. In further generations of homozygous offspring the methylation spread into the transcribed region and gene activity was completely repressed also in nonvascular cells. The results indicate that different stages are involved in DNA methylation-correlated gene inactivation, and that at least one of them may involve the attraction of a sequence and methylation-specific DNA-binding protein.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific silencing of a transgene in rice

Klöti

Potrykus

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…In vitro studies have, however, shown that methylation at Sp 1 site does not inhibit its binding to its cognate site. On the other hand, methylation of cytosines at MRE-d sequence increases binding of MTF-1 several fold (Radtke et al, 1996). Only MLTF binding to MLTF/ USF binding site has been shown to be inhibited by methylation (Watt and Molloy, 1990).…”

Section: Discussionmentioning

confidence: 99%

Silencing of metallothionein-I gene in mouse lymphosarcoma cells by methylation

Majumder¹,

Ghoshal²,

Li³

et al. 1999

Oncogene

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Metallothionein-I (MT-I) gene is silenced by methylation of CpG islands in mouse lymphosarcoma P1798 cells but not in the thymus, the cell type from which the tumor was derived. Bisul®te genomic sequencing revealed that all 21 CpG dinucleotides present within 7216 bp to +1 bp with respect to transcription start site are methylated in the tumor cell line, but none is methylated in the thymus. The lymphosarcoma cells induced MT-I in response to heavy metals only after demethylation with 5-azacytidine (5-AsaC). The electrophoretic mobility shift assay using speci®c oligonucleotide probes showed that the key transcription factors regulating MT-I gene (e.g., MTF-1, Sp 1 and MLTF/USF) are active in P1798 cells. In vivo footprinting of the proximal promoter region showed that none of the metal regulatory elements (MREs) or MLTF/USF are occupied in response to heavy metals. Demethylation of the lymphosarcoma cells with 5-AzaC resulted in constitutive footprinting at MLTF/ARE, and zinc-inducible footprinting at MRE-c, MRE-d and MREe sites. Demethylation of just 10 ± 20% of the CpG islands was sucient to render the gene inducible by cadmium or zinc. The MT-I induction persisted in the cancer cells for several generations even after withdrawal of 5-AzaC from the culture medium.

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“…This happens through two basic mechanisms, including direct interference with transcription factor binding and the recruitment of specialized methyl-DNA binding proteins. For the former, many transcription factors have methylation statusspecific interactions with DNA, including E2F, Krox-20, and CREB (31,126,252). Methylation of CpG nucleotides abrogates normal binding of these proteins to DNA, leading to transcriptional repression.…”

Section: Dna Methylationmentioning

confidence: 99%

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Cyr

Domann

2011

Antioxidants & Redox Signaling

242

168

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Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD + , S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551-589.

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Differential Sensitivity of Zinc Finger Transcription Factors MTF-1, Sp1 and Krox-20 to CpG Methylation of Their Binding Sites

Cited by 34 publications

References 48 publications

Tissue-specific silencing of a transgene in rice

Tissue-specific silencing of a transgene in rice

Silencing of metallothionein-I gene in mouse lymphosarcoma cells by methylation

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

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