Epigenetics and the control of epithelial sodium channel expression in collecting duct.
Kidney Int. 2008 Sep 24. [Epub ahead of print]
Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone BC.
1Division of Nephrology, Hypertension and Renal Transplantation, University of Florida College of Medicine, Gainesville, Florida, USA.
In eukaryotic nuclei, genomic DNA is compacted with histone and nonhistone proteins into a dynamic polymer termed chromatin. Reorganization of chromatin structure through histone modifications, the action of chromatin factors, or DNA methylation, can profoundly change gene expression. These epigenetic modifications allow heritable and potentially reversible changes in gene functioning to occur without altering the DNA sequence, thus extending the information potential of the genetic code. This review provides an introduction to epigenetic concepts for renal investigators and an overview of our work detailing an epigenetic pathway for aldosterone signaling and the control of epithelial Na(+) channel-alpha (ENaCalpha) subunit gene expression in the collecting duct. This new pathway involves a nuclear repressor complex, consisting of histone H3 Lys-79 methyltransferase disruptor of telomeric silencing-1a (Dot1a), ALL1 fused gene from chromosome 9 (Af9), a sequence-specific DNA-binding protein that binds the ENaCalpha promoter, and potentially other nuclear proteins. This complex regulates targeted histone H3 Lys-79 methylation of chromatin associated with the ENaCalpha promoter, thereby suppressing its transcriptional activity. Aldosterone disrupts the Dot1a-Af9 interaction by serum- and glucocorticoid-induced kinase-1 phosphorylation of Af9, and inhibits Dot1a and Af9 expression, resulting in histone H3 Lys-79 hypomethylation at specific subregions, and derepression of the ENaCalpha promoter. The Dot1a-Af9 pathway may also be involved in the control of genes implicated in renal fibrosis and hypertension.Kidney International advance online publication, 24 September 2008; doi:10.1038/ki.2008.475.
PMID: 18818687 [PubMed - as supplied by publisher]
Monday, November 10, 2008
The evaluation of level of epigenetic indicator--5-methylcytosine in smoking and non-smoking patients with mild essential hypertension.
The evaluation of level of epigenetic indicator--5-methylcytosine in smoking and non-smoking patients with mild essential hypertension.
Przegl Lek. 2007;64(10):695-7.
Smolarek I, Olszewski J, Naskret-Barciszewska M, Wyszko E, Jabłecka A.
Zaktad Farmakologii Klinicznej, Katedry Kardiologii, Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu. iwosmo@wp.pl
5-methylcytosine (m5C, 5mC) is a nucleotide occurring naturally in genomic DNA and play an important role in regulation of genes expression. Methylation of cytosine in DNA is an epigenetic modification and different intrinsic and extrinsic factors can influence on its level. For example, it is subject to modification and/or degradation by the free radicals which are commonly present in environment of human, among others the cigarette smoke. The reactions of m5C with free radicals lead to origination of many products which effect is decrease of level of m5C in DNA (hypomethylation) and excessive expression of genes inducing development of different diseases, especially cardiovascular system diseases. The aim of the study was statement if exist differences of level of 5-methylcytosine in DNA between smoking and non-smoking patients suffering from mild essential hypertension. The study group was composed of 30 patients suffering from mild essential hypertension (21 females and 40 males) aged from 18 to 55 years (32.4+/-10.3 years). The group of smoker was composed of 13 patients (5 females and 8 males) and the group of non-smokers was composed of 17 patients (7 females and 10 males). 3-5 ml of blood was sampled on EDTA and then thin-layer chromatography analysis of 5-methylcytosine level in DNA after previous enzymatic hydrolysis of DNA and radioactive phosphorus labeling [32p] was performed. The mean level of 5-methylcytosine (m5C) were 1.30+/-0.56 [%] in non-smoking patients, and 1.28+/-0.42 [%] in smoking patients suffering from mild essential hypertension. There is no significant statistically differences between non-smoking and smoking patients (p>0.4). In the study the following conclusion was drawn: the level of m5C in DNA of patients suffering from mild essential hypertension in the study is independent of smoking (p>0.4) in patients with mild essential hypertension. However it supposes, out of regard for theoretic datum suggestive such influence, the study should be performed in more frequent group of patients.
PMID: 18409288 [PubMed - indexed for MEDLINE]
Przegl Lek. 2007;64(10):695-7.
Smolarek I, Olszewski J, Naskret-Barciszewska M, Wyszko E, Jabłecka A.
Zaktad Farmakologii Klinicznej, Katedry Kardiologii, Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu. iwosmo@wp.pl
5-methylcytosine (m5C, 5mC) is a nucleotide occurring naturally in genomic DNA and play an important role in regulation of genes expression. Methylation of cytosine in DNA is an epigenetic modification and different intrinsic and extrinsic factors can influence on its level. For example, it is subject to modification and/or degradation by the free radicals which are commonly present in environment of human, among others the cigarette smoke. The reactions of m5C with free radicals lead to origination of many products which effect is decrease of level of m5C in DNA (hypomethylation) and excessive expression of genes inducing development of different diseases, especially cardiovascular system diseases. The aim of the study was statement if exist differences of level of 5-methylcytosine in DNA between smoking and non-smoking patients suffering from mild essential hypertension. The study group was composed of 30 patients suffering from mild essential hypertension (21 females and 40 males) aged from 18 to 55 years (32.4+/-10.3 years). The group of smoker was composed of 13 patients (5 females and 8 males) and the group of non-smokers was composed of 17 patients (7 females and 10 males). 3-5 ml of blood was sampled on EDTA and then thin-layer chromatography analysis of 5-methylcytosine level in DNA after previous enzymatic hydrolysis of DNA and radioactive phosphorus labeling [32p] was performed. The mean level of 5-methylcytosine (m5C) were 1.30+/-0.56 [%] in non-smoking patients, and 1.28+/-0.42 [%] in smoking patients suffering from mild essential hypertension. There is no significant statistically differences between non-smoking and smoking patients (p>0.4). In the study the following conclusion was drawn: the level of m5C in DNA of patients suffering from mild essential hypertension in the study is independent of smoking (p>0.4) in patients with mild essential hypertension. However it supposes, out of regard for theoretic datum suggestive such influence, the study should be performed in more frequent group of patients.
PMID: 18409288 [PubMed - indexed for MEDLINE]
Sunday, August 17, 2008
11ß-Hydroxysteroid dehydrogenase type 2 & Hypertension
Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension.
Atherosclerosis. 2008 Aug;199(2):323-7. Epub 2008 Feb 7.
Friso S, Pizzolo F, Choi SW, Guarini P, Castagna A, Ravagnani V, Carletto A, Pattini P, Corrocher R, Olivieri O.
Department of Clinical and Experimental Medicine, University of Verona School of Medicine, Verona, Italy. simonetta.friso@univr.it
BACKGROUND: Lower activity of 11 beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) classically induces hypertension by leading to an altered tetrahydrocortisol- versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. Recent cell culture and animal studies suggest a role for promoter methylation, a major epigenetic feature of DNA, in regulation of HSD11B2 expression. Little is known, however, of human HSD11B2 epigenetic control and its relationship with the onset of hypertension. OBJECTIVE: To explore the possible relevance of HSD11B2 promoter methylation, by examining human peripheral blood mononuclear cell (PBMC) DNA and urinary THFs/THE ratio as a biochemical indicator of 11beta-HSD2 activity, in blood pressure control. METHODS: Twenty-five essential hypertensives and 32 subjects on prednisone therapy were analyzed, the latter to investigate 11beta-HSD2 function in the development of hypertension. RESULTS: Elevated HSD11B2 promoter methylation was associated with hypertension developing in glucocorticoid-treated patients in parallel with a higher urinary THFs/THE ratio. Essential hypertensives with elevated urinary THFs/THE ratio also showed higher HSD11B2 promoter methylation. CONCLUSIONS: These results show a clear link between the epigenetic regulation through repression of HSD11B2 in PBMC DNA and hypertension.
PMID: 18178212 [PubMed - in process]
Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension.
Am J Hypertens. 2005 Aug;18(8):1091-8.
Mariniello B, Ronconi V, Sardu C, Pagliericcio A, Galletti F, Strazzullo P, Palermo M, Boscaro M, Stewart PM, Mantero F, Giacchetti G.
Division of Endocrinology, Department of Internal Medicine, Università Politecnica delle Marche, Umberto I Hospital, Ancona, Italy.
BACKGROUND: The HSD11B2 gene, encoding the kidney isoenzyme 11beta-hydroxysteroid dehydrogenase, is a candidate for essential hypertension. We previously showed that the frequency of shorter alleles of a CA repeat polymorphism in the first intron of 11beta-HSD2 gene was significantly higher among salt-sensitive than salt-resistant individuals with hypertension. The aim of the study was to analyze the HSD11B2 gene to assess whether some of its variants might be involved in hypertension. METHODS: Exons 2, 3, 4, and 5 were screened by polymerase chain reaction-single-strand conformation polymorphism analysis in 292 hypertensive patients and 163 control subjects. The samples with variant electrophoretic patterns at single-strand conformation polymorphism were re-analyzed using an automated DNA sequencer. A case-control study was then performed by comparing genotype frequencies in hypertensive and normotensive subjects. RESULTS: Analysis of the HSD11B2 showed that in hypertensive patients there is a higher prevalence of two associated polymorphisms, Thr156/Thr(C468A) in exon 2 (ex2) and Glu178/Glu(G534A) in exon 3 (ex3), than in normotensive subjects (9% v 2.4%). This association did not correlate with salt sensitivity. C468A alone correlates significantly with hypertension (9%) and was identified only in 3% of control subjects (P < .05), whereas G534A was identified also in about 7% of normotensive subjects. The urinary free cortisol/urinary free cortisone ratio (UFF/UFE) was significantly higher in hypertensive patients compared with control subjects (P < .01). CONCLUSIONS: Two different polymorphisms of the HSD11B2 gene were observed. The association of both polymorphisms was significantly higher in hypertensive subjects than in control subjects. Its role should be further investigated, but it could be related to other mutations in the promoter region of HSD11B2 or to the modulation of 11beta-HSD2 mRNA processing in hypertensive subjects.
PMID: 16109323 [PubMed - indexed for MEDLINE]
Role of HSD11B2 polymorphisms in essential hypertension and the diuretic response to thiazides.
Kidney Int. 2005 Feb;67(2):631-7.
Williams TA, Mulatero P, Filigheddu F, Troffa C, Milan A, Argiolas G, Parpaglia PP, Veglio F, Glorioso N.
Hypertension Unit, Department of Medicine and Experimental Oncology, University of Torino, Torino, Italy.
BACKGROUND: The renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thereby protecting the nonselective mineralocorticoid (MR) receptor from occupation by glucocorticoids. Loss-of-function mutations in the gene encoding 11beta HSD2 (HSD11B2) result in overstimulation of the MR and cause salt-sensitive hypertension. METHODS: We have investigated the role of HSD11B2 in hypertension in 377 genetically homogeneous essential hypertensives from North Sardinia. RESULTS: Thirty of these patients displayed increased urinary cortisol metabolite ratios (greater than or equal to 2) (tetrahydrocortisol [THF]+allotetrahydrocortisol [aTHF]/tetrahydrocortisone [THE]) reflecting a mild reduction in 11beta HSD2 activity. No mutations in HSD11B2 were detected in these patients. All 377 patients were genotyped for a CA repeat microsatellite in intron 1 of HSD11B2 and a G534A polymorphism in exon 3 of HSD11B2. CA repeat length was associated with the (THF+aTHF)/THE ratio, which in turn was significantly related to PRA levels. No associations were found between the G354A polymorphism and the other parameters. There were no differences in blood pressure (BP) levels between HSD11B2 genotypes, but in a subgroup of 91 patients that underwent diuretic therapy, CA repeat length was strongly associated with the BP response to hydrochlorothiazide. CONCLUSION: This study highlights the role of this HSD11B2 polymorphism in sodium handling and is consistent with a role in the BP response to thiazide diuretics.
PMID: 15673310 [PubMed - indexed for MEDLINE]
Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity
The FASEB Journal. 2007;21:3618-3628.
Rasoul Alikhani-Koupaei*, Fatemeh Fouladkou*, Pierre Fustier*, Bruno Cenni, Arya M. Sharma, Hans-Christian Deter, Brigitte M. Frey*,1 and Felix J. Frey*
* Nephrology and Hypertension and Clinical Research; Institute for Clinical Chemistry, University Hospital of Berne, Berne, Switzerland; Canada Research Chair for Cardiovascular Obesity Research and Management, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada; and Department of Psychosomatics and Psychotherapy, Charité Campus Benjamin Franklin, Berlin
1Correspondence: Department of Nephrology and Hypertension, University Hospital, Freiburgstrasse 15, 3010 Bern-Inselspital, Switzerland. E-mail: brigitte.frey@dkf.unibe.ch
'//-->
Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a role in essential hypertension and the sensitivity of blood pressure to dietary salt. Nonconservative mutations in the coding region are extremely rare and do not explain the variable 11beta-HSD2 activity. We focused therefore on the 5'-regulatory region and identified and characterized the first promoter polymorphisms. Transfections of variants G-209A and G-126A into SW620 cells reduced promoter activity and affinity for activators nuclear factor 1 (NF1) and Sp1. Chromatin immunoprecipitation revealed Sp1, NF1, and glucocorticoid receptor (GR) binding to the HSD11B2 promoter. Dexamethasone induced expression of mRNA and activity of HSD11B2. GR and/or NF1 overexpression increased endogenous HSD11B2 mRNA and activity. GR complexes cooperated with NF1 to activate HSD11B2, an effect diminished in the presence of the G-209A variant. When compared to salt-resistant subjects (96), salt-sensitive volunteers (54) more frequently had the G-209A variant, higher occurrence of alleles A4/A7 of polymorphic microsatellite marker, and higher urinary ratios of cortisol to cortisone metabolites. First, we conclude that the mechanism of glucocorticoid-induced HSD11B2 expression is mainly mediated by cooperation between GR and NF1 on the HSD11B2 promoter and, second, that the newly identified promoter variants reduce activity and cooperation of cognate transcription factors, resulting in diminished HSD11B2 transcription, an effect favoring salt sensitivity.—Alikhani-Koupaei, R., Fouladkou, F., Fustier, P., Cenni, B., Sharma, A. M., Deter, H.-C., Frey, B. M., Frey, F. J. Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity.
11ß-Hydroxysteroid dehydrogenase type 2 activity is associated with left ventricular mass in essential hypertension.
European Heart Journal 2005 26(5):498-504; doi:10.1093/eurheartj/ehi070
Nicola Glorioso1,*, Fabiana Filigheddu1, Paolo Pinna Parpaglia2, Aldo Soro1, Chiara Troffa1, Giuseppe Argiolas1 and Paolo Mulatero3
1Hypertension and Cardiovascular Prevention Centre, ASL n.1-University of Sassari, Italy2Emergency Department, ASL n.1, Sassari, Italy3Hypertension Centre, University of Torino, Italy
Received 9 July 2004; revised 4 October 2004; accepted 28 October 2004; online publish-ahead-of-print 15 December 2004.
* Corresponding author. Tel:/fax: +39 079 228388. E-mail address: glorioso@uniss.it
'//-->
Aims Left ventricular mass (LVM) is under the control of aldosterone and angiotensin II in experimental hypertension, but the effect of aldosterone on LVM is controversial in essential hypertension (EH). Some EH patients show a mild impairment of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) activity without clinical features of the syndrome of apparent mineralocorticoid excess, where the incomplete cortisol-to-cortisone conversion leads to glucocorticoid-mediated mineralocorticoid effects. The mineralocorticoid receptor and 11ß-HSD2 are co-expressed in human heart. We investigated whether LVM may be regulated by glucocorticoids in EH patients.
Methods and results The ratio between 24 h urinary tetrahydro derivatives of cortisol and cortisone (THFs/THE), plasma renin activity, 24 h urinary aldosterone, blood pressure, and LVM indexed for height2.7 (LVMh2.7) were analysed in 493 never-treated hypertensives and 98 normotensives. THFs/THE was associated with LVMh2.7 in hypertensives and normotensives (r=0.32, P<0.001, and r=0.17, P=0.04, respectively) and persisted after adjusting for confounders (multiple regression analysis). Body mass index, sex, recumbent plasma renin activity, and THFs/THE accounted for 26.1% of LVMh2.7 variation. Urinary aldosterone was not correlated with LVMh2.7.
Conclusion We suggest that glucocorticoids may take part in the regulation of LVM in EH patients as a function of 11ß-HSD2 activity, and contribute to the target organ damage associated with essential hypertension.
Link for Full Text: http://eurheartj.oxfordjournals.org/cgi/reprint/26/5/498
Atherosclerosis. 2008 Aug;199(2):323-7. Epub 2008 Feb 7.
Friso S, Pizzolo F, Choi SW, Guarini P, Castagna A, Ravagnani V, Carletto A, Pattini P, Corrocher R, Olivieri O.
Department of Clinical and Experimental Medicine, University of Verona School of Medicine, Verona, Italy. simonetta.friso@univr.it
BACKGROUND: Lower activity of 11 beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) classically induces hypertension by leading to an altered tetrahydrocortisol- versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. Recent cell culture and animal studies suggest a role for promoter methylation, a major epigenetic feature of DNA, in regulation of HSD11B2 expression. Little is known, however, of human HSD11B2 epigenetic control and its relationship with the onset of hypertension. OBJECTIVE: To explore the possible relevance of HSD11B2 promoter methylation, by examining human peripheral blood mononuclear cell (PBMC) DNA and urinary THFs/THE ratio as a biochemical indicator of 11beta-HSD2 activity, in blood pressure control. METHODS: Twenty-five essential hypertensives and 32 subjects on prednisone therapy were analyzed, the latter to investigate 11beta-HSD2 function in the development of hypertension. RESULTS: Elevated HSD11B2 promoter methylation was associated with hypertension developing in glucocorticoid-treated patients in parallel with a higher urinary THFs/THE ratio. Essential hypertensives with elevated urinary THFs/THE ratio also showed higher HSD11B2 promoter methylation. CONCLUSIONS: These results show a clear link between the epigenetic regulation through repression of HSD11B2 in PBMC DNA and hypertension.
PMID: 18178212 [PubMed - in process]
Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension.
Am J Hypertens. 2005 Aug;18(8):1091-8.
Mariniello B, Ronconi V, Sardu C, Pagliericcio A, Galletti F, Strazzullo P, Palermo M, Boscaro M, Stewart PM, Mantero F, Giacchetti G.
Division of Endocrinology, Department of Internal Medicine, Università Politecnica delle Marche, Umberto I Hospital, Ancona, Italy.
BACKGROUND: The HSD11B2 gene, encoding the kidney isoenzyme 11beta-hydroxysteroid dehydrogenase, is a candidate for essential hypertension. We previously showed that the frequency of shorter alleles of a CA repeat polymorphism in the first intron of 11beta-HSD2 gene was significantly higher among salt-sensitive than salt-resistant individuals with hypertension. The aim of the study was to analyze the HSD11B2 gene to assess whether some of its variants might be involved in hypertension. METHODS: Exons 2, 3, 4, and 5 were screened by polymerase chain reaction-single-strand conformation polymorphism analysis in 292 hypertensive patients and 163 control subjects. The samples with variant electrophoretic patterns at single-strand conformation polymorphism were re-analyzed using an automated DNA sequencer. A case-control study was then performed by comparing genotype frequencies in hypertensive and normotensive subjects. RESULTS: Analysis of the HSD11B2 showed that in hypertensive patients there is a higher prevalence of two associated polymorphisms, Thr156/Thr(C468A) in exon 2 (ex2) and Glu178/Glu(G534A) in exon 3 (ex3), than in normotensive subjects (9% v 2.4%). This association did not correlate with salt sensitivity. C468A alone correlates significantly with hypertension (9%) and was identified only in 3% of control subjects (P < .05), whereas G534A was identified also in about 7% of normotensive subjects. The urinary free cortisol/urinary free cortisone ratio (UFF/UFE) was significantly higher in hypertensive patients compared with control subjects (P < .01). CONCLUSIONS: Two different polymorphisms of the HSD11B2 gene were observed. The association of both polymorphisms was significantly higher in hypertensive subjects than in control subjects. Its role should be further investigated, but it could be related to other mutations in the promoter region of HSD11B2 or to the modulation of 11beta-HSD2 mRNA processing in hypertensive subjects.
PMID: 16109323 [PubMed - indexed for MEDLINE]
Role of HSD11B2 polymorphisms in essential hypertension and the diuretic response to thiazides.
Kidney Int. 2005 Feb;67(2):631-7.
Williams TA, Mulatero P, Filigheddu F, Troffa C, Milan A, Argiolas G, Parpaglia PP, Veglio F, Glorioso N.
Hypertension Unit, Department of Medicine and Experimental Oncology, University of Torino, Torino, Italy.
BACKGROUND: The renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thereby protecting the nonselective mineralocorticoid (MR) receptor from occupation by glucocorticoids. Loss-of-function mutations in the gene encoding 11beta HSD2 (HSD11B2) result in overstimulation of the MR and cause salt-sensitive hypertension. METHODS: We have investigated the role of HSD11B2 in hypertension in 377 genetically homogeneous essential hypertensives from North Sardinia. RESULTS: Thirty of these patients displayed increased urinary cortisol metabolite ratios (greater than or equal to 2) (tetrahydrocortisol [THF]+allotetrahydrocortisol [aTHF]/tetrahydrocortisone [THE]) reflecting a mild reduction in 11beta HSD2 activity. No mutations in HSD11B2 were detected in these patients. All 377 patients were genotyped for a CA repeat microsatellite in intron 1 of HSD11B2 and a G534A polymorphism in exon 3 of HSD11B2. CA repeat length was associated with the (THF+aTHF)/THE ratio, which in turn was significantly related to PRA levels. No associations were found between the G354A polymorphism and the other parameters. There were no differences in blood pressure (BP) levels between HSD11B2 genotypes, but in a subgroup of 91 patients that underwent diuretic therapy, CA repeat length was strongly associated with the BP response to hydrochlorothiazide. CONCLUSION: This study highlights the role of this HSD11B2 polymorphism in sodium handling and is consistent with a role in the BP response to thiazide diuretics.
PMID: 15673310 [PubMed - indexed for MEDLINE]
Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity
The FASEB Journal. 2007;21:3618-3628.
Rasoul Alikhani-Koupaei*, Fatemeh Fouladkou*, Pierre Fustier*, Bruno Cenni, Arya M. Sharma, Hans-Christian Deter, Brigitte M. Frey*,1 and Felix J. Frey*
* Nephrology and Hypertension and Clinical Research; Institute for Clinical Chemistry, University Hospital of Berne, Berne, Switzerland; Canada Research Chair for Cardiovascular Obesity Research and Management, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada; and Department of Psychosomatics and Psychotherapy, Charité Campus Benjamin Franklin, Berlin
1Correspondence: Department of Nephrology and Hypertension, University Hospital, Freiburgstrasse 15, 3010 Bern-Inselspital, Switzerland. E-mail: brigitte.frey@dkf.unibe.ch
'//-->
Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a role in essential hypertension and the sensitivity of blood pressure to dietary salt. Nonconservative mutations in the coding region are extremely rare and do not explain the variable 11beta-HSD2 activity. We focused therefore on the 5'-regulatory region and identified and characterized the first promoter polymorphisms. Transfections of variants G-209A and G-126A into SW620 cells reduced promoter activity and affinity for activators nuclear factor 1 (NF1) and Sp1. Chromatin immunoprecipitation revealed Sp1, NF1, and glucocorticoid receptor (GR) binding to the HSD11B2 promoter. Dexamethasone induced expression of mRNA and activity of HSD11B2. GR and/or NF1 overexpression increased endogenous HSD11B2 mRNA and activity. GR complexes cooperated with NF1 to activate HSD11B2, an effect diminished in the presence of the G-209A variant. When compared to salt-resistant subjects (96), salt-sensitive volunteers (54) more frequently had the G-209A variant, higher occurrence of alleles A4/A7 of polymorphic microsatellite marker, and higher urinary ratios of cortisol to cortisone metabolites. First, we conclude that the mechanism of glucocorticoid-induced HSD11B2 expression is mainly mediated by cooperation between GR and NF1 on the HSD11B2 promoter and, second, that the newly identified promoter variants reduce activity and cooperation of cognate transcription factors, resulting in diminished HSD11B2 transcription, an effect favoring salt sensitivity.—Alikhani-Koupaei, R., Fouladkou, F., Fustier, P., Cenni, B., Sharma, A. M., Deter, H.-C., Frey, B. M., Frey, F. J. Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity.
11ß-Hydroxysteroid dehydrogenase type 2 activity is associated with left ventricular mass in essential hypertension.
European Heart Journal 2005 26(5):498-504; doi:10.1093/eurheartj/ehi070
Nicola Glorioso1,*, Fabiana Filigheddu1, Paolo Pinna Parpaglia2, Aldo Soro1, Chiara Troffa1, Giuseppe Argiolas1 and Paolo Mulatero3
1Hypertension and Cardiovascular Prevention Centre, ASL n.1-University of Sassari, Italy2Emergency Department, ASL n.1, Sassari, Italy3Hypertension Centre, University of Torino, Italy
Received 9 July 2004; revised 4 October 2004; accepted 28 October 2004; online publish-ahead-of-print 15 December 2004.
* Corresponding author. Tel:/fax: +39 079 228388. E-mail address: glorioso@uniss.it
'//-->
Aims Left ventricular mass (LVM) is under the control of aldosterone and angiotensin II in experimental hypertension, but the effect of aldosterone on LVM is controversial in essential hypertension (EH). Some EH patients show a mild impairment of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) activity without clinical features of the syndrome of apparent mineralocorticoid excess, where the incomplete cortisol-to-cortisone conversion leads to glucocorticoid-mediated mineralocorticoid effects. The mineralocorticoid receptor and 11ß-HSD2 are co-expressed in human heart. We investigated whether LVM may be regulated by glucocorticoids in EH patients.
Methods and results The ratio between 24 h urinary tetrahydro derivatives of cortisol and cortisone (THFs/THE), plasma renin activity, 24 h urinary aldosterone, blood pressure, and LVM indexed for height2.7 (LVMh2.7) were analysed in 493 never-treated hypertensives and 98 normotensives. THFs/THE was associated with LVMh2.7 in hypertensives and normotensives (r=0.32, P<0.001, and r=0.17, P=0.04, respectively) and persisted after adjusting for confounders (multiple regression analysis). Body mass index, sex, recumbent plasma renin activity, and THFs/THE accounted for 26.1% of LVMh2.7 variation. Urinary aldosterone was not correlated with LVMh2.7.
Conclusion We suggest that glucocorticoids may take part in the regulation of LVM in EH patients as a function of 11ß-HSD2 activity, and contribute to the target organ damage associated with essential hypertension.
Link for Full Text: http://eurheartj.oxfordjournals.org/cgi/reprint/26/5/498
Friday, August 1, 2008
Epigenetics Web-links
During my search for online resources, I found several useful websites on epigenetics research. I have written below the selected ones for easy access.
NOVA: Epigenetics
http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html
NOVA: RNAi
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
Science: Functional Epigenomics resources
http://www.sciencemag.org/feature/plus/sfg/resources/res_epigenetics.dtl
DNA Methylation Database
http://www.methdb.de/
Human Epigenome Project
http://www.epigenome.org/
Epigenetics Papers: Israel Barrantes’s Blog
http://epigenetica.blogspot.com/
The Epigenetics Center in the Institute for Basic Biomedical Sciences
Johns Hopkins School of Medicine
http://www.hopkinsmedicine.org/ibbs/research/epigenetics/
Centre for Epigenetics
http://www.epigenetics.dk/
Epigenetics Research
http://www.epidna.com/
Epigenetic and Methylation Station
http://www.epigeneticstation.com/
Epigenetics and Chromatin: Open Access Journal
http://www.epigeneticsandchromatin.com/
The Epigenome Network of Excellence
http://www.epigenome-noe.net/
The Epigenetics Database
http://www.epidna.com/database.php
Protocol Online
http://www.protocol-online.org/
The RNAi Web
http://www.rnaiweb.com/
NOVA: Epigenetics
http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html
NOVA: RNAi
http://www.pbs.org/wgbh/nova/sciencenow/3210/02.html
Science: Functional Epigenomics resources
http://www.sciencemag.org/feature/plus/sfg/resources/res_epigenetics.dtl
DNA Methylation Database
http://www.methdb.de/
Human Epigenome Project
http://www.epigenome.org/
Epigenetics Papers: Israel Barrantes’s Blog
http://epigenetica.blogspot.com/
The Epigenetics Center in the Institute for Basic Biomedical Sciences
Johns Hopkins School of Medicine
http://www.hopkinsmedicine.org/ibbs/research/epigenetics/
Centre for Epigenetics
http://www.epigenetics.dk/
Epigenetics Research
http://www.epidna.com/
Epigenetic and Methylation Station
http://www.epigeneticstation.com/
Epigenetics and Chromatin: Open Access Journal
http://www.epigeneticsandchromatin.com/
The Epigenome Network of Excellence
http://www.epigenome-noe.net/
The Epigenetics Database
http://www.epidna.com/database.php
Protocol Online
http://www.protocol-online.org/
The RNAi Web
http://www.rnaiweb.com/
Computational epigenetics.
Bioinformatics. 2008 Jan 1;24(1):1-10. Epub 2007 Nov 17.
Computational epigenetics.
Bock C, Lengauer T.
Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de
Epigenetic research aims to understand heritable gene regulation that is not directly encoded in the DNA sequence. Epigenetic mechanisms such as DNA methylation and histone modifications modulate the packaging of the DNA in the nucleus and thereby influence gene expression. Patterns of epigenetic information are faithfully propagated over multiple cell divisions, which makes epigenetic regulation a key mechanism for cellular differentiation and cell fate decisions. In addition, incomplete erasure of epigenetic information can lead to complex patterns of non-Mendelian inheritance. Stochastic and environment-induced epigenetic defects are known to play a major role in cancer and ageing, and they may also contribute to mental disorders and autoimmune diseases. Recent technical advances such as ChIP-on-chip and ChIP-seq have started to convert epigenetic research into a high-throughput endeavor, to which bioinformatics is expected to make significant contributions. Here, we review pioneering computational studies that have contributed to epigenetic research. In addition, we give a brief introduction into epigenetics-targeted at bioinformaticians who are new to the field-and we outline future challenges in computational epigenetics.
PMID: 18024971 [PubMed - indexed for MEDLINE]
Link for Full Text: http://bioinformatics.oxfordjournals.org/cgi/content/full/24/1/1
Computational epigenetics.
Bock C, Lengauer T.
Max-Planck-Institut für Informatik, Saarbrücken, Germany. cbock@mpi-inf.mpg.de
Epigenetic research aims to understand heritable gene regulation that is not directly encoded in the DNA sequence. Epigenetic mechanisms such as DNA methylation and histone modifications modulate the packaging of the DNA in the nucleus and thereby influence gene expression. Patterns of epigenetic information are faithfully propagated over multiple cell divisions, which makes epigenetic regulation a key mechanism for cellular differentiation and cell fate decisions. In addition, incomplete erasure of epigenetic information can lead to complex patterns of non-Mendelian inheritance. Stochastic and environment-induced epigenetic defects are known to play a major role in cancer and ageing, and they may also contribute to mental disorders and autoimmune diseases. Recent technical advances such as ChIP-on-chip and ChIP-seq have started to convert epigenetic research into a high-throughput endeavor, to which bioinformatics is expected to make significant contributions. Here, we review pioneering computational studies that have contributed to epigenetic research. In addition, we give a brief introduction into epigenetics-targeted at bioinformaticians who are new to the field-and we outline future challenges in computational epigenetics.
PMID: 18024971 [PubMed - indexed for MEDLINE]
Link for Full Text: http://bioinformatics.oxfordjournals.org/cgi/content/full/24/1/1
Stability and flexibility of epigenetic gene regulation in mammalian development.
Nature. 2007 May 24;447(7143):425-32.
Stability and flexibility of epigenetic gene regulation in mammalian development.
Reik W.
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, UK. wolf.reik@bbsrc.ac.uk
During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences--transposons, imprinted genes and pluripotency-associated genes--in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.
PMID: 17522676 [PubMed - indexed for MEDLINE]
Link for Full Text: http://www.nature.com/nature/journal/v447/n7143/full/nature05918.html
Stability and flexibility of epigenetic gene regulation in mammalian development.
Reik W.
Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, UK. wolf.reik@bbsrc.ac.uk
During development, cells start in a pluripotent state, from which they can differentiate into many cell types, and progressively develop a narrower potential. Their gene-expression programmes become more defined, restricted and, potentially, 'locked in'. Pluripotent stem cells express genes that encode a set of core transcription factors, while genes that are required later in development are repressed by histone marks, which confer short-term, and therefore flexible, epigenetic silencing. By contrast, the methylation of DNA confers long-term epigenetic silencing of particular sequences--transposons, imprinted genes and pluripotency-associated genes--in somatic cells. Long-term silencing can be reprogrammed by demethylation of DNA, and this process might involve DNA repair. It is not known whether any of the epigenetic marks has a primary role in determining cell and lineage commitment during development.
PMID: 17522676 [PubMed - indexed for MEDLINE]
Link for Full Text: http://www.nature.com/nature/journal/v447/n7143/full/nature05918.html
Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression.
J Clin Invest. 2004 Oct;114(8):1146-57.
Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression.
Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM.
Department of Nephrology and Hypertension, University Hospital of Berne, Berne UNK 3010, Switzerland.
The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11 beta-hydroxyglucocorticoids. Variable activity of 11 beta HSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11 beta HSD2, HSD11B2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2'-deoxycytidine and procainamide enhanced the transcription and activity of the 11 beta HSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG-binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.
PMID: 15489962 [PubMed - indexed for MEDLINE]
Link for Full Text: http://www.jci.org/articles/view/21647
Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression.
Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM.
Department of Nephrology and Hypertension, University Hospital of Berne, Berne UNK 3010, Switzerland.
The enzyme 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11 beta-hydroxyglucocorticoids. Variable activity of 11 beta HSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11 beta HSD2, HSD11B2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2'-deoxycytidine and procainamide enhanced the transcription and activity of the 11 beta HSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG-binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.
PMID: 15489962 [PubMed - indexed for MEDLINE]
Link for Full Text: http://www.jci.org/articles/view/21647
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