DNA methylation directs a time-dependent repression of transcription initiation

Kass, Stefan U.; Landsberger, Nicoletta; Wolffe, Alan P.

doi:10.1016/s0960-9822(97)70086-1

Cited by 340 publications

(242 citation statements)

References 40 publications

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“…The aberrant cytosine methylation of the BRCA1 5′ regulatory region is, most likely, the first epigenetic event. Previous studies have shown that a methylated reporter construct transfected into mammalian cells was able to transcribe the reporter gene for 8 h (31,32). After 8 h, however, the methylated construct became transcriptionally inert which coincided with alterations in the nucleosomal array and an inability of RNA polymerase to bind the regulatory region.…”

Section: Discussionmentioning

confidence: 98%

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Rice¹

2000

Nucleic Acids Research

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BRCA1 expression is repressed by aberrant cytosine methylation in sporadic breast cancer. We hypothesized that aberrant cytosine methylation of the BRCA1 promoter was associated with the transcriptionally repressive effects of histone hypoacetylation and chromatin condensation. To address this question, we developed an in vitro model of study using normal cells and sporadic breast cancer cells with known levels of BRCA1 transcript to produce a 1.4 kb 5-methylcytosine map of the BRCA1 5′ CpG island. While all cell types were densely methylated upstream of -728 relative to BRCA1 transcription start, all normal and BRCA1 expressing cells were non-methylated downstream of -728 suggesting that this region contains the functional BRCA1 5′ regulatory region. In contrast, the non-BRCA1 expressing UACC3199 cells were completely methylated at all 75 CpGs. Chromatin immunoprecipitations showed that the UACC3199 cells were hypoacetylated at both histones H3 and H4 in the BRCA1 promoter compared to non-methylated BRCA1 expressing cells. The chromatin of the methylated UACC3199 BRCA1 promoter was inaccessible to DNA-protein interactions. These data indicate that the epigenetic effects of aberrant cytosine methylation, histone hypoacetylation and chromatin condensation act together in a discrete region of the BRCA1 5′ CpG island to repress BRCA1 transcription in sporadic breast cancer.

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Section: Discussionmentioning

confidence: 98%

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Rice¹

2000

Nucleic Acids Research

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“…The oocyte is known to repress methylated DNA very effectively (Kass et al 1997;Jones et al 1998). We used a plasmid containing the hsp70 promoter driving the expression of the CAT reporter gene, the expression of which was determined by quantitative RT-PCR.…”

Section: Transcription From Methylated Promoters In Early Embryosmentioning

confidence: 99%

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Bogdanović

Long²,

Heeringen³

et al. 2011

Genome Res.

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DNA methylation is a tightly regulated epigenetic mark associated with transcriptional repression. Next-generation sequencing of purified methylated DNA obtained from early Xenopus tropicalis embryos demonstrates that this genome is heavily methylated during blastula and gastrula stages. Although DNA methylation is largely absent from transcriptional start sites marked with histone H3 lysine 4 trimethylation (H3K4me3), we find both promoters and gene bodies of active genes robustly methylated. In contrast, DNA methylation is absent in large H3K27me3 domains, indicating that these two repression pathways have different roles. Comparison with chromatin state maps of human ES cells reveals strong conservation of epigenetic makeup and gene regulation between the two systems. Strikingly, genes that are highly expressed in pluripotent cells and in Xenopus embryos but not in differentiated cells exhibit relatively high DNA methylation. Therefore, we tested the repressive potential of DNA methylation using transient and transgenic approaches and show that methylated promoters are robustly transcribed in blastula-and gastrula-stage embryos, but not in oocytes or late embryos. These findings have implications for reprogramming and the epigenetic regulation of pluripotency and differentiation and suggest a relatively open, pliable chromatin state in early embryos followed by reestablished methylation-dependent transcriptional repression during organogenesis and differentiation.

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“…In these cases the promoter CpG islands associated with the silent genes are largely methylated [48]. In addition, in mammalian females the inactivation of X-chromosome is dependent on DNA methylation, CpGs sites in promoters of the genes on the inactive X chromosome are methylated and the genes are transcriptionally silent [49]. A role for DNA methylation in tissue specific gene expression and differentiation has also been proposed.…”

Section: Cpg Dinucleotides Location and Func-tionmentioning

confidence: 99%

Dynamic and reversibility of heterochromatic gene silencing in human disease

et al. 2005

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In eukaryotic organisms cellular fate and tissue specific gene expression are regulated by the activity of proteins known as transcription factors that by interacting with specific DNA sequences direct the activation or repression of target genes. The post genomic era has shown that transcription factors are not the unique key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, post-translational modifications of histone proteins, remodeling of nucleosomes and expression of small regulatory RNAs also contribute to regulation of gene expression, determination of cell and tissue specificity and assurance of inheritance of gene expression levels. The relevant contribution of epigenetic mechanisms to a proper cellular function is highlighted by the effects of their deregulation that cooperate with genetic alterations to the development of various diseases and to the establishment and progression of tumors.

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DNA methylation directs a time-dependent repression of transcription initiation

Cited by 340 publications

References 40 publications

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Dynamic and reversibility of heterochromatic gene silencing in human disease

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