DNA methylation and the regulation of globin gene expression

Busslinger, Meinrad; Hurst, J.; Flavell, Richard A.

doi:10.1016/0092-8674(83)90150-2

Cited by 431 publications

(206 citation statements)

References 23 publications

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“…It has been suggested that methylation of cytosine in CpG dinucleotides in the 5 0 and the 3 0 flanking region represses gene expression by preventing transcription factors from binding to their target. 13,22,23 In this study, we observed that the 5 0 region of the SDF1 gene was unmethylated even in PBMCs where the SDF1 gene was not expressed. As for the 3 0 UTR of the SDF1b gene, by contrast, we found site-specific demethylation in the region around the polymorphic site at np 801 in the EBV-transformed LCLs that express the SDF-1 mRNA.…”

Section: Discussionmentioning

confidence: 58%

“…12 However, this kind of experiments does not realize the original genome conditions of the transfected gene. For instance, status of DNA methylation, one of the regulatory factors in gene expression, 13,14 would not be identical in the chromosomes and in the transfected vectors. To shed light on the relation of the SDF1-G801A polymorphism with gene expression, cells from a number of individuals with different genotypes are thus required.…”

Section: Introductionmentioning

confidence: 99%

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The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

2003

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The effects of the SDF1-3 0 A on AIDS progression have been attributed to the altered amount of stromal cell-derived factor 1 (SDF-1). However, the contribution of the SDF1-G801A polymorphism to SDF-1 expression is still unclear. In contrast to fresh peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express the SDF-1 mRNA. Using EBV-transformed LCLs from 42 individuals with different genotypes, we investigated the SDF-1 mRNA levels and methylation status in the SDF1 gene. Both in PBMCs and in EBV-transformed LCLs, CpG dinucleotides in the 5 0 region of the SDF1 gene were unmethylated. As for the 3 0 untranslated region (3 0 UTR), by contrast, CpG dinucleotides were methylated in PBMCs, whereas site-specific demethylation around the polymorphic site was detected in EBV-transformed LCLs. The levels of the demethylation were correlated with the SDF-1 mRNA levels. However, the genotype for the SDF1-G801A polymorphism did not significantly alter the SDF-1 mRNA levels. The allele preferences in transcription and methylation were also absent in the heterozygous cells. In conclusion, this study suggested a contribution of site-specific demethylation in the 3 0 UTR to the SDF1 gene expression, but did not show any evidence for the contribution of the SDF1-G801A polymorphism to the amount of the SDF-1 mRNA.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

2003

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“…For instance, it has been shown to affect tissue specific gene regulation, parental imprinting, and X-inactivation (for reviews, see Busslinger et al, 1983;Cedar, 1988;Lyon, 1988;Weissbach et al, 1989). Studies on both transferred genes (Busslinger et al, 1983;Hadchouel et al, 1987;Ledent et al, 1990;Rimoldi et al, 1991) and endogenous genes (Stein et al, 1983;Hansen and Gartler, 1990) have shown a correlation between 0 1994 WILEY-LISS, INC. specific methylation patterns of DNA sequences and the status of specific gene expression. Further evidence for this relationship comes from studies employing a DNA methylation inhibitor, 5-azacytidine (5-AzaC) (Glover and Leyland-Jone, 19871, in both animals and cultured cells.…”

mentioning

confidence: 99%

Demethylation in the 5′‐flanking region of mouse cellular retinoic acid binding protein‐I gene is associated with its high level of expression in mouse embryos and facilitates its induction by retinoic acid in P19 embryonal carcinoma cells

Wei

Lee

1994

Developmental Dynamics

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The mouse cellular retinoic acid binding protein-I (CRABP-I) gene is specifically up-regulated by retinoic acid (RA) in P19 mouse embryonal carcinoma cells, and its expression in animals is spatially and temporally restricted to RA-sensitive tissues during embryonic development. This study demonstrates that, in adult mouse tissues and P19 cells where the expression of CRABP-I is detected at the basal level, the 5'-flanking region of the CRABP-I gene is hypermethylated at the C residues of all the H p a I1 sites. Conversely, in mouse embryos during early stages of development when the expression of CRABP-I gene is detected at a much higher level, this region is demethylated at these H p a I1 sites. In P19, enhancement on the RA-induced up-regulation of CRABP-I can be observed in cells treated with 5-azacytidine (5-AzaC) in conjunction with RA, where partial demethylation in the 5'-flanking region of CRABP-I gene is observed. Nuclear run-on experiments indicate that increased message levels of CRABP-I in P19 cells can be accounted for, at least partially, by increases in its transcription rates. The induction of retinoic acid receptor (RAR) p by RA can also be enhanced by 5-AzaC, but to a much lesser degree. In contrast, all the H p a I1 sites in the structural gene portion, at least in the first two exons, are fully demethylated at the C residues. o 1994 WiIey-Liss, Inc.

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“…It has been reported that the most effective transcriptional repression by CpG methylation is observed when the promoter/leader region is methylated [2,3,8]. On the other hand, in a transient transfection *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, for almost all repression experiments, entire recombinant plasmids are methylated in vitro just before transfection into mammalian cells [6,8,10,14,15,23]. To analyze the effect of methylating specific DNA segments on transcription, several different methods have been developed to obtain regionally methylated plasmid DNAS [2,4,9,28]. We have devised a method to efficiently ligate a methylated oligonucleotide into the plasmid backbone by using non-palindromic restriction enzyme sites.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG‐rich regions

et al. 1996

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Cytosine methylation of binding sites for transcription factors is a straightforward mechanism to prevent transcription, while data on an indirect mechanism, by methylation outside of the factor binding sites, are still scarce. We have studied the latter effect using a model promoter construct. For this, a 69 bp G + C rich DNA segment with a cluster of 14 CpG sites was inserted between upstream iexA sites and the TATA box. Transcription was measured in transient transfection assays with IexA-VP16 as an activating factor. When the entire plasmid was methylated at all CpGs before transfection, transcription was blocked (to 3% residual activity), whereas transcription was only mildly inhibited (to 60%) by methylation of a control plasmid that lacked the 69 bp CpG cluster. However, the effect could not simply be attributed to methylation of the CpG cluster: neither a methylated CpG cluster in an otherwise methylation-free reporter gene plasmid, nor the methylated plasmid with an unmethylated CpG cluster, inhibited transcription considerably (69% and 44% remaining activity, respectively). The data presented here suggest that a minimal length of methylated DNA in the promoter is required for repression, and imply that concomitant methylation of CpGs in the promoter region and in remote sequences can cooperatively block transcription, without the need to methylate any binding sites for transcription factors. We also note that the cooperation for a negative effect described here bears an analogy to transcriptional activation, where a promoter often cooperates with a remote enhancer.

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DNA methylation and the regulation of globin gene expression

Cited by 431 publications

References 23 publications

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein–Barr virus-transformed lymphoblastoid cells

Demethylation in the 5′‐flanking region of mouse cellular retinoic acid binding protein‐I gene is associated with its high level of expression in mouse embryos and facilitates its induction by retinoic acid in P19 embryonal carcinoma cells

Transcriptional repression by methylation: cooperativity between a CpG cluster in the promoter and remote CpG‐rich regions

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