J Clin Invest. 2004 Oct;114( 8 ):1146-57. Related Articles, Links
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]
T-cell dna methylation declines as we age and is likely a cause of autoimmune disease (Yung et al. 1995).
Inherited defects of the methylation process would be expected to occur in humans and might lead to genomic instability during embryonic development or later in life. Later expression of the defect might predispose to a variety of malignant neoplasms. If activation of transposons could not be prevented during early embryogenesis, affected individuals might suffer new mutations that affect most or all cells of the embryo proper. Different mutations would be expected in different individuals who inherit the methylation defect, and various affected members of a single family might exhibit different new dominant diseases. http://www.csu.edu.au/learning/ncgr/gpi/jclub/9712/Index.html
http://www.qimr.edu.au/research/topics/ ... ation.html
Changes in gene expression that result in aberrant cell behaviour are the hallmark of a cancer cell. Contained within the human genome of DNA are thousands of CG dinucleotides. These are subject to a chemical modification called 'methylation', a process that can inhibit the expression of a gene. DNA methylation has many functions in normal cells, including suppression of 'tumor causing' genes and regulation of tissue specific genes. Recently DNA methylation has been shown to play a role in the initiation and progression of cancer cells. Adverse DNA methylation has been shown to inactivate tumour suppressor genes, promote chromosome instability and lead to increased mutations in the genome. These may all lead to cancer. Scientists at QIMR and around the world are trying to find out what turns such a normal mechanism of cell regulation into an initiator of cancer and how to stop or reverse the process.
QIMR Scientists are investigating how DNA methylation determines gene expression in the following research areas:
• Control of cytokine expression
• Regulation of membrane receptors
• Genomic imprinting
Lab Head: Professor Anne Kelso
Our laboratory is interested in the development and control of specialised functions in T lymphocytes, especially their expression of genes for cytokines and mediators of cytolytic function. Our work on the behaviour of single T cells during primary immune responses has given us the following picture of early events in T cell specialisation.
Naive T cells have the flexibility to express different cytokines depending on the signals they receive during activation and many retain this flexibility through extended cell division. Individual patterns of cytokine expression are highly diverse, even within activated T cell populations with interferon-y or interleukin-4 biassed cytokine profiles. These biases therefore reflect a population average rather than a homogeneous cellular response. Regulatory signals, such as IL-4 itself, alter the probability that certain genes are expressed in a given cell, rather than acting in an absolute manner. Like cytokines, the mediators of cytolytic activity, perforin and granzymes, are differentially expressed in individual T cells. The T cell pool therefore comprises cells with striking functional flexibility so that population shifts in gene expression patterns can achieve a focussed response to a pathogen.
A major interest in the last year has been the regulation of cytotoxicity and cytokine profiles in newly-activated CD8 T cells, especially under the influence of IL-4. In the absence of this cytokine in vitro, and during influenza virus infection in vivo, we find that most effector T cells express one or more of the mRNAs for perforin, granzymes A and B, and IFN-y. Very few express IL-4 itself. Primary activation in the presence of IL-4, however, leads some naive CD8 T cells to develop into effector cells that express both IFN-y and IL-4 but display minimal cytolytic activity. Investigation of the molecular mechanisms that underlie this functional impairment suggest that IL-4 exerts dual actions, limiting both the recognition and lysis of target cells by reducing surface CD8 expression and perforin and granzyme production, respectively. An important next step is to evaluate the significance of this differentiative pathway for T cells when IL-4 is present during an immune response in vivo.
Sharon, you're our hormone expert.......what have you found about this?):
did you find the ACTH paradox, also? What do you make of that?
In an odd way, it does make sense to discover that ACTH stays within normal limits in MS, though, because if ACTH was involved at all in MS, then the disease itself would either present itself as Addison's or Cushing's, not MS. Right? And for some strange reason, we don't even find Addison's or Cushing's as co-existing with MS!? How odd!!!
“So called “normal” lab values for cortisol include all but the most extreme values”, too much cortisol, more than 2 standard deviations above the mean, results in a diagnosis of Cushing’s Syndrome, and too little cortisol, more than 2 standard deviations below the mean, results in a diagnosis of Addison’s disease.
“Most hormones have such a broad range of plasma levels within a normal population. As a consequence, the level of a hormone in an individual may be halved or doubled (and thus be abnormal for that person) but still be within the so-called normal range.”
Over the long term, elevated cortisol levels can be as detrimental to overall health as elevated cholesterol is for heart disease or excessive blood sugar is for diabetes. Aside from that, elevated cortisol levels make you fat, kill your sex drive, shrink your brain, squelch your immune system, and generally make you feel terrible.
that both male and female hormones are made in the adrenals of each person, regardless of gender.
In males, the adrenals provide a secondary source of testosterone and are the exclusive source of the female hormone estrogen (referred to collectively as estrone, estradiol and estriol.)
In females, the adrenals provide a secondary source of estrogen and progesterone, and are the nearly exclusive supplier of testosterone.
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