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
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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
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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

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/

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

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

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 modification of the renin-angiotensin system in the fetal programming of hypertension.

Circ Res. 2007 Mar 2;100(4):520-6. Epub 2007 Jan 25.
Epigenetic modification of the renin-angiotensin system in the fetal programming of hypertension.
Bogdarina I, Welham S, King PJ, Burns SP, Clark AJ.
Centre for Endocrinology, Barts & the London, Queen Mary University of London, UK.
Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT(1b) angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT(1b) gene in the adrenal is significantly undermethylated, and that in vitro, AT(1b) gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension.
PMID: 17255528 [PubMed - indexed for MEDLINE]

Link for Full Text: http://circres.ahajournals.org/cgi/content/full/100/4/520

Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome.

Environ Health Perspect. 2006 Apr;114(4):567-72.
Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome.
Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL.
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Genistein, the major phytoestrogen in soy, is linked to diminished female reproductive performance and to cancer chemoprevention and decreased adipose deposition. Dietary genistein may also play a role in the decreased incidence of cancer in Asians compared with Westerners, as well as increased cancer incidence in Asians immigrating to the United States. Here, we report that maternal dietary genistein supplementation of mice during gestation, at levels comparable with humans consuming high-soy diets, shifted the coat color of heterozygous viable yellow agouti (A(vy/a) offspring toward pseudoagouti. This marked phenotypic change was significantly associated with increased methylation of six cytosine-guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. The extent of this DNA methylation was similar in endodermal, mesodermal, and ectodermal tissues, indicating that genistein acts during early embryonic development. Moreover, this genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from obesity. Thus, we provide the first evidence that in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome.
PMID: 16581547 [PubMed - indexed for MEDLINE]

Link for Full Text: http://www.ehponline.org/members/2006/8700/8700.html

Epigenetic differences arise during the lifetime of monozygotic twins.

Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9. Epub 2005 Jul 11.
Epigenetic differences arise during the lifetime of monozygotic twins.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M.
Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.
PMID: 16009939 [PubMed - indexed for MEDLINE]

Link for Full Text: http://www.pnas.org/content/102/30/10604.full