Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites

Lenz, Bernd; Bleich, Stefan; Beutler, Sonja; Schlierf, Beate; Schwager, Katja; Reulbach, Udo; Kornhuber, Johannes; Bönsch, Dominikus

doi:10.1016/j.yexcr.2006.09.004

Cited by 32 publications

(24 citation statements)

References 29 publications

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“…38 In cultured cells, Hcy has been shown to induce gene-specific DNA hypomethylation regulating the expression of Hcyinduced endoplasmic reticulum protein (HERP) and an imprinted gene H19. 39,40 However, some reports indicate that hypomethylation can be followed by the global hypermethylation of DNA through mechanisms not yet understood. 39 In fact, leukocytic DNA from an SAH hydrolase-deficient individual paradoxically has been found to be hypermethylated.…”

Section: Discussionmentioning

confidence: 99%

“…39,40 However, some reports indicate that hypomethylation can be followed by the global hypermethylation of DNA through mechanisms not yet understood. 39 In fact, leukocytic DNA from an SAH hydrolase-deficient individual paradoxically has been found to be hypermethylated. 41 Our discovery that Hcy-induced FGF2 downregulation could be attenuated by 5-aza-dC, a well-known demethylating reagent, 42 also supported the paradoxical hypermethylation of the FGF2 promoter as illustrated in Figure 7.…”

Section: Discussionmentioning

confidence: 99%

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Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation

Chang

Lee

et al. 2008

Circulation Research

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Abstract-Homocysteine (Hcy) contributes to atherogenesis and angiostasis by altering the phenotype of arterial endothelial cells (ECs). The present study was aimed at elucidating potential mechanisms by which Hcy can slow EC proliferation and induce EC apoptosis, thereby disrupting endothelial integrity. Given the strong mitogenic and antiapoptotic properties of fibroblast growth factor (FGF)2, we examined whether Hcy can modulate its expression. In cultured human coronary and bovine aortic ECs, Hcy exerted time-and concentration-dependent (0 to 500 mol/L) reduction of the mRNA and protein levels of FGF2, whereas vascular endothelial growth factor expression was not affected until Hcy reached a proapoptotic 500 mol/L. By testing a panel of signal transduction inhibitors, we found that the Hcy-induced downregulation of FGF2 was specifically attenuated by pertussis toxin, an inhibitor of Gi protein signaling. Hcy induced cell cycle arrest at the G 1 /S transition and increased TUNEL-positive apoptotic cells in a graded manner. These effects were effectively counteracted by exogenous FGF2. Reporter gene assays showed that Hcy downregulated FGF2 by transcriptional repression of the gene promoter encompassed in a CpG dinucleotide-rich island. This region was heavily methylated at the cytosine residues by Hcy despite decreased methylation potential (S-adenosylmethionine to S-adenosylhomocysteine ratio). Normal levels of FGF2 transcription were restored to ECs simultaneously exposed to Hcy and 5-aza-deoxycytidine. We conclude that homocysteine disrupts the growth and survival of ECs through a G protein-mediated pathway associated with altered promoter DNA methylation and the transcriptional repression of FGF2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation

Chang

Lee

et al. 2008

Circulation Research

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“…Alternatively, increased MTHFR expression would increase methionine levels for production of S-adenosylmethionine and methylation reactions. This increase could contribute to the general increase in DNA methylation induced by homocysteine (48) or to specific methylation changes associated with ER stress, such as the methylation modification of nucleosomes at the GRP78 promoter (49). ER stress can induce the UPR, which can lead to cell death as well as to prosurvival mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Increases the Expression of Methylenetetrahydrofolate Reductase through the IRE1 Transducer

Leclerc

Rozen

2008

Journal of Biological Chemistry

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Methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate and homocysteine metabolism, influences many cellular processes including methionine and nucleotide synthesis, methylation reactions, and maintenance of homocysteine at nontoxic levels. Mild deficiency of MTHFR is common in many populations and modifies risk for several complex traits including vascular disease, birth defects, and cancer. We recently demonstrated that MTHFR can be up-regulated by NF-B, an important mediator of cell survival that is activated by endoplasmic reticulum (ER) stress. This observation, coupled with the reports that homocysteine can induce ER stress, prompted us to examine the possible regulation of MTHFR by ER stress. We found that several well characterized stress inducers (tunicamycin, thapsigargin, and A23187) as well as homocysteine could increase Mthfr mRNA and protein in Neuro-2a cells. The induction of MTHFR was also observed after overexpression of inositol-requiring enzyme-1 (IRE1) and was inhibited by a dominant-negative mutant of IRE1. Because IRE1 triggers c-Jun signaling, we examined the possible involvement of c-Jun in up-regulation of MTHFR. Transfection of c-Jun and two activators of c-Jun (LiCl and sodium valproate) increased MTHFR expression, whereas a reported inhibitor of c-Jun (SP600125) and a dominant-negative derivative of c-Jun N-terminal kinase-1 reduced MTHFR activation. We conclude that ER stress increases MTHFR expression and that IRE1 and c-Jun mediate this activation. These findings provide a novel mechanism by which the ER can regulate homeostasis and allude to an important role for MTHFR in cell survival.

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“…For H69, however, the constructs harbouring fragment pf1 led to a significant reduction of relative luciferase activity by 80% compared with the empty plasmid. Transcription factor prediction identified a putative TATA box (TCTATTCTCA), a binding site for TFIID (GGCTGGG), a CREB half-site (CRE, CGTCA) in reverse orientation and many other common transcription To assay functionality, we performed site-directed mutagenesis ( Figure 3a) following a previously described approach (Lenz et al, 2006). As a consequence, relative luciferase activity of the construct pf1 CREB À, harbouring a mutated CRE, was statistically significantly reduced as compared with relative luciferase activity of pf1 in the cell lines H128 and H69, and was also assessed in HEK293 (human embryonic kidney) cells ( Figure 3b; Supplementary Table 2).…”

Section: Expression Analysis Of Nrsf/rest and Target Genesmentioning

confidence: 99%

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

et al. 2010

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Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites

Cited by 32 publications

References 29 publications

Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation

Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation

Endoplasmic Reticulum Stress Increases the Expression of Methylenetetrahydrofolate Reductase through the IRE1 Transducer

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

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