Mast Cell-/Basophil-specific Transcriptional Regulation of Human l-Histidine Decarboxylase Gene by CpG Methylation in the Promoter Region

Kuramasu, Atsuo; Saito, Hirohisa; Suzuki, Shigeharu; Watanabe, Tetsu; Ohtsu, Hiroshi

doi:10.1074/jbc.273.47.31607

Cited by 69 publications

(46 citation statements)

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“…In addition, cis element modifications, such as DNA methylation, could also be important in regulating gene expression during growth and development [17±19]. DNA methylation was recently shown to contribute to the cell-specific expression of the gene encoding l-histidine decarboxylase and cyclin D1 [16,20]. We have also found that demethylation of specific CpG sites, as well as a methylation-sensitive transcription factor, contribute to the sex-specific expression of the Cyp2d-9 gene and to the cell-specific expression of the thyrotropin receptor gene [21,22].…”

Section: Discussionmentioning

confidence: 99%

“…We also showed that the binding sites for Sp1 within the leptin gene promoter are located between nt ±115 and nt ±70. The in vitro binding of proteins to DNA does not always reflect binding in vivo [16,26]. Indeed, Sp1 can bind to a promoter and activate transcription in vitro even when the CpG site within the Sp1 binding site is methylated.…”

Section: Discussionmentioning

confidence: 99%

“…Methylation of the reporter plasmid was done as described [16]. Briefly, the plasmid, pLepLuc-115 or pLepLuc-70, was digested with Hind III and Xba I, and the fragment was gel-purified.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

2002

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“…These results suggested that Sp1 might in part determine the tissue specificity of the mAbcc6 gene expression. Because tissue specificity can be determined by methylation at Sp1 sites, the binding of Sp1 transcription factor was suggested to protect the genomic DNA from being methylated [40] [41] [42] [43]. Aranyi et al [28] described the presence of a CpG island in the human proximal promoter and suggested that methylation at this site could influence the tissue specific gene expression of ABCC6.…”

Section: Discussionmentioning

confidence: 99%

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Douet

VanWart

Heller

et al. 2006

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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SUMMARYMutations in an ABC transporter gene called ABCC6 are responsible for pseudoxanthoma elasticum (PXE), a rare heritable disease characterized by elastic fiber calcification in skin, ocular and vascular tissues. The presumed function of this ABC transporter is to export metabolites from polarized cells. However, the endogenous substrate(s) are unknown and the exact relationship with elastic fibers is unclear. As ABCC6 is expressed at high level only in liver and kidneys, tissues seemingly unrelated to the PXE phenotype, we explored the transcriptional regulation of the murine Abcc6 gene to define transcriptional regulation conferring tissue specificity and to gather clues on its possible biological function. We cloned 2.9 kb of the mAbcc6 5′-flanking region and several deletion constructs linked to a luciferase reporter gene. We delineated a proximal promoter and a liver-specific enhancer region. We also demonstrated that the proximal region is a TATA-less promoter requiring an intact CCAATbox and Sp1 binding for its basal activity. By using reporter assays and chromatin immunoprecipitations, we showed that HNF4α and surprinsingly, NF-E2, enhanced the mAbcc6 promoter activity. The involvement of both HNF4α and NF-E2 in the mAbcc6 gene regulation suggests that Abcc6 might be involved in a detoxification processes related to hemoglobin or heme.

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“…Moreover, by using different protein kinase inhibitors, it has been shown that the mechanism of pituitary adenylate cyclase-activating polypeptide regulation is distinct from gastrin regulation of the HDC promoter (18). Interestingly, the DNA methylation state of the HDC promoter region has been also shown to control HDC gene expression in both the human and mouse (19,20). The HDC promoter region was demethylated in the HDC-expressing cell lines, such as the differentiated mast cell line MC9 and the erythroleukemia cell line DS19.…”

mentioning

confidence: 99%

Kruppel-like Factor 4 (KLF4) Represses Histidine Decarboxylase Gene Expression through an Upstream Sp1 Site and Downstream Gastrin Responsive Elements

Liu

Langlois

et al. 2004

Journal of Biological Chemistry

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Histidine decarboxylase (HDC) is the enzyme that catalyzes the conversion of histidine to histamine, a bioamine that plays an important role in allergic responses, inflammation, neurotransmission, and gastric acid secretion. Previously, we demonstrated that gastrin activates HDC promoter activity in a gastric cancer (AGS-E) cell line through three overlapping downstream promoter elements. In the current study, we used the yeast one-hybrid strategy to identify nuclear factors that bind to these three elements. Among eight positives from the one-hybrid screen, we identified Kruppel-like factor 4 (KLF4) (previously known as gut-enriched Kruppel-like factor (GKLF)) as one factor that binds to the gastrin responsive elements in the HDC promoter. Electrophoretic mobility shift assays confirmed that KLF4 is able to bind all three gastrin responsive elements. In addition, transient cotransfection experiments showed that overexpression of KLF4 dose dependently and specifically inhibited HDC promoter activity. Regulation of HDC transcription by KLF4 was confirmed by changes in the endogenous HDC messenger RNA by KLF4 small interfering RNA and KLF4 overexpression. We further showed that KLF4 inhibits HDC promoter activity by competing with Sp1 at the upstream GC box and also independently by binding the three downstream gastrin responsive elements. Taken together, these results indicate that KLF4 can act to repress HDC gene expression by Sp1-dependent and -independent mechanisms.Histamine is a bioamine that plays an important role in many physiological processes, including allergy, inflammation, neurotransmission, and gastric acid secretion (1-3). Histidine decarboxylase (HDC) 1 is the single enzyme that converts histidine to histamine (4). HDC is expressed in many different cell types, including mast cells, skin cells, platelets, and basophils. However, in the adult mammals, HDC is highly expressed in enterochromaffin-like cells, where the HDC activity is tightly regulated by a gut peptide hormone, gastrin (5). HDC regulation occurs at both the transcriptional and post-translational levels, the latter by proteolytic processing through the ubiquitin-proteasome pathway (6, 7).HDC promoter activity is up-regulated by several different stimuli, including gastrin (8), phorbol ester phorbol 12-myristate 13-acetate (8 -11), oxidative stress (12), thrombopointin (13), and Helicobacter pylori infection (14, 15). Whereas not all of the cis-acting DNA elements or the transcriptional factors involved in regulation of HDC transcription have been identified, three GC-rich gastrin responsive elements located downstream of the transcription initiation site have been characterized in the human HDC promoter region (16,17). Through the use of Southwestern blot and UV cross-linking, the sizes of the three gastrin responsive element-binding factors have previously been assessed at 53, 33, and 110 kDa of apparent molecular mass, respectively (16,17). Recently, a neural peptide pituitary adenylate cyclase-activating polypeptide has been reporte...

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Mast Cell-/Basophil-specific Transcriptional Regulation of Human l-Histidine Decarboxylase Gene by CpG Methylation in the Promoter Region

Cited by 69 publications

References 50 publications

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

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

HNF4α and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression

Kruppel-like Factor 4 (KLF4) Represses Histidine Decarboxylase Gene Expression through an Upstream Sp1 Site and Downstream Gastrin Responsive Elements

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