Methyl-CpG-Binding Protein MeCP2 Represses Sp1-Activated Transcription of the Human Leukosialin Gene When the Promoter Is Methylated

Kudo, Shinichi

doi:10.1128/mcb.18.9.5492

Cited by 137 publications

(111 citation statements)

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“…Transcriptional repressor proteins that have been shown to be functional in this process include the methyl-CpG-binding proteins-1 and -2 (MeCP1, MeCP2) and methyl-CpG binding domain family members (MBD1, MBD2a, MBD2b, and MBD4) (6,22,44). MeCP2 is a relatively abundant chromosomal protein, whose localization in the nucleus is primarily dependent on CpG methylation (32,44). It contains an 80-aa long methyl-CpG-binding domain (that binds to a methylated-CpG dinucleotide) and a transcriptional repressor domain.…”

Section: Discussionmentioning

confidence: 99%

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

Lapchak¹,

Melter²,

Pal³

et al. 2004

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 99%

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

Lapchak¹,

Melter²,

Pal³

et al. 2004

American Journal of Physiology-Renal Physiology

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“…Indeed, Sp1 can bind to a promoter and activate transcription in vitro even when the CpG site within the Sp1 binding site is methylated. The methyl-CpG-binding protein, MeCP2, however, has been found to bind to DNA containing single methylated CpG site, and to repress Sp1-activated transcription of the human leukosialin gene when the promoter is methylated [27]. A methyl-CpG-binding protein, such as, MeCP2 could therefore recognize the methylated and demethylated leptin promoter and interact with Sp1 and/or other transcription factors such as Lp1 and contribute to the expression of the leptin gene during 3T3-L1 differentiation.…”

Section: Discussionmentioning

confidence: 99%

DNA demethylation modulates mouse leptin promoter activity during the differentiation of 3T3-L1 cells

2002

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During the differentiation of 3T3-L1 preadipocytes to adipocytes, transcriptional activators and repressors regulate the expression of many adipocyte-specific genes [1±4]. In addition, DNA methylation could also play an important role during the process of adipocyte differentiation. We recently showed that methylation of specific CpG sites of the GLUT4 gene and a methylation sensitive transcription factor, contribute to GLUT4 gene regulation during 3T3-L1 differentiation [5]. Similar mechanisms could also regulate the expression of other genes induced during adipocyte differentiation.Leptin, a major hormonal regulator of appetite and fat cell mass, is one of these adipocyte-specific genes [6,7]. It is secreted by adipose tissue in response to a high content of body fat. Thus, mice lacking a functional leptin gene develop hyperphagia, hy- Abstract Aims/hypothesis. The mouse leptin gene, a major hormonal regulator of appetite and fat cell mass, expresses during the differentiation of 3T3-L1 preadipocytes to adipocytes. To determine if DNA methylation is involved in regulating the expression of the leptin gene, we examined the methylation status and methylation-sensitive transcription factors during 3T3-L1 differentiation. Methods. DNase I footprinting, electrophoretic mobility-shift assays, and a Southwestern analysis were carried out using nuclear extracts from preadipocytes and adipocytes. Promoter activity was measured by luciferase assays. The CpG methylation pattern was determined.Results. Transient transfection of reporter constructs with the leptin promoter showed that preadipocytes that do not transcribe the leptin gene show enough transactivation, suggesting the presence of an additional regulatory mechanism. We identified eight CpG sites in the promoter up to nt ±161, all of which were highly methylated ( > 92 %) in preadipocytes. Seven of these sites showed a varying degree of demethylation during differentiation, while the site at nt ±54 remained methylated. In electrophoretic mobilityshift assays, DNA fragments from nt ±115 to nt ±70 generated a methylation-sensitive band with nuclear extracts from preadipocytes when the CpG sites were methylated. Southwestern analysis identified a 52 kM r protein that binds strongly to the methylated probes. Promoter activity was reduced by methylation of the CpG sites up to nt ±115, but not up to nt ±70. Conclusion/interpretation. These results suggest that methylation of specific CpG sites between nt ±115 and nt ±70 and a methylation-sensitive protein could contribute to leptin gene expression during adipocyte differentiation in 3T3-L1 cells. [Diabetologia (2002) 45: 140±148]

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“…Methylation of CpG dinucleotides located within DNA recognition elements may interfere with the binding of transcription factors, which inhibits transcription (Siegfried et al, 1999). Methylated CpG dinucleotides interfere with SP1 binding and further the reduced binding of Sp1 may be involved in suppression of transcriptional activity of the genes such as AQP5, and CLDN4 (Clark et al, 1997;Honda et al, 2006;Kudo, 1998;Mancini et al, 1999;Motegi et al, 2005;Zhu et al, 2003). In agreement with these findings, we observed that the normal breast epithelial cells MCF-10A had a heavily methylated potential SP1-binding site, the ninth CG of the LIF promoter, while benign and carcinoma MCF10 variants did not.…”

Section: Discussionmentioning

confidence: 99%

“…RNAi-mediated knockdown of LIF results in breast cancer cells with decreased cell growth and decreased colony forming ability Most evidence about LIF suggests that it stimulates the proliferation of most carcinoma cell lines, including the estrogendependent MCF-7 and the estrogen-independent SK-BR30 breast cancer cell lines (Douglas et al, 1997;1998;KellokumpuLehtinen et al, 1996). To understand if a LIF deficiency affects the growth or survival of MCF10 cells, we performed knockdown experiments in noninvasive carcinoma MCF-10DCIS.com cells, which have high levels of LIF expression.…”

Section: Upregulation Of the Lif Gene Is Correlated With Development mentioning

confidence: 99%

“…Though there is no consensus on which epigenetic mechanism initiates and steers this communication, a feedback loop may exist between histone modification and DNA methylation (Vaissiere et al, 2008). The recruitment of the methyl-CpGbinding protein (MeCP2) mediates the repression by DNA methylation (Kudo, 1998). DNA methylation has been recently linked to methylation of Lys9 of histone H3, which is a histone mark for transcriptional repression.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

Shin

Park

Jang

2011

Molecules and Cells

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The interleukin 6 family of cytokines including leukemia inhibitory factor (LIF) regulates the progression of several types of cancer. However, although LIF overexpression during breast cancer progression was observed in our previous report, the molecular mechanisms responsible for this deregulation remain largely unknown. Here we show that LIF expression is epigenetically up-regulated via DNA demethylation and changes in histone methylation status within its promoter region in the isogenic MCF10 model. Bisulfite sequencing revealed the CpG pairs within the promoter region are hypermethylated in normal breast epithelial cells, but extensively demethylated as breast cancer progresses. In agreement with the DNA methylation pattern, our chromatin immunoprecipitation showed that inactive epigenetic marks such as MeCP2 occupancy and histone H3-Lys9-dimethylation significantly decreased during the progression to breast cancer but an active histone mark was increased in an inverse manner. Also, the occupancy of the transcription factor Sp1, which has higher affinity for hypomethylated CpGs, increased. RNAimediated knockdown of LIF expression resulted in a significant reduction of cell growth and colony formation in breast cancer cells, suggesting the potential role of LIF-LIF receptor axis in autocrine stimulation of cancer cells. Collectively, our data suggest that the epigenetic up-regulation of the LIF gene likely play an important role in the development of breast cancer.

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Methyl-CpG-Binding Protein MeCP2 Represses Sp1-Activated Transcription of the Human Leukosialin Gene When the Promoter Is Methylated

Cited by 137 publications

References 54 publications

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

DNA demethylation modulates mouse leptin promoter activity during the differentiation of 3T3-L1 cells

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

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