Is anyone else wondering about this besides me? Anyone care to take a stab at answering this?
Can XMRV Cause A Methylation Cycle Block?
- Thread starter caledonia
- Start date
From the Doc I saw this week, he thinks that the methylation block, (believes its genetic) causes the viruses, toxins to build.....I like this theory. Homeopath claims viruses cant live in the body without mercury that is why they put vaccines in it as the carrier. Also said vaccines are cultured in mercury.
If methylation is not working properly, like a blocked drain, we get a build up of mercury and other metals plus other pathogens feeding off this as a result...no where to exit the body as a result.
If methylation is not working properly, like a blocked drain, we get a build up of mercury and other metals plus other pathogens feeding off this as a result...no where to exit the body as a result.
Here's something that Gerwyn posted from another thread that answers my question in the affirmative:
"XMRV shows a preference for integrating within the start codons of certain genes. It can act as a pseudogene sometimes called a gene switch. If it gets into some genes the effects might not be noticeable or lead to very mild vague unwellness.
If it integrates within a gene which regulates other genes then we have all the ingredients for a party.
One such example is the gene complex that regulates the immune system by kicking off the innate or inflammatory response called TFNalpha. This is the gene that interferon alpha binds to.
The real doozy however is that XMRV integrates into the creb gene regulating what is called the CREB/CRE system
The CREB gene is responsible for the protection of nerve cells maintaining plasticity and preventing the natural tendancy towards neuron death.
The CREB /CRE system controls gene expression all over the body including those that ensure mitochondrial function directly and indirectly.
As a nice little twist mitochondrial mutations, however small and on their own, may produce someone prone to infection for example.will magnify any abnormality in the CREB/system. Mitochondrial mutations and creb transcriptional abnormalities can interact, turning the party into a full scale riot.
Creb CRE produce proteins which control the binding of interferon alpha to the TFN alphs gene blocking this binding will have a serious effect on. It is possible to block interferon binding of alpha but enhance B producing the innate responses observed in patients with ME and of course lead to a higher level of free interferon alpha that Judy M was talking about
So it's just not getting the XMRV but how it interacts with essential gene systems or not that determines having symptoms the severity of those symptoms and the spread of bodily systems dysregulated.
CREB proteins also control the expression of enzymes essential for the function of the methylation system dysfunction would lead to at least a partial block--The key one is methionine synthase."
"XMRV shows a preference for integrating within the start codons of certain genes. It can act as a pseudogene sometimes called a gene switch. If it gets into some genes the effects might not be noticeable or lead to very mild vague unwellness.
If it integrates within a gene which regulates other genes then we have all the ingredients for a party.
One such example is the gene complex that regulates the immune system by kicking off the innate or inflammatory response called TFNalpha. This is the gene that interferon alpha binds to.
The real doozy however is that XMRV integrates into the creb gene regulating what is called the CREB/CRE system
The CREB gene is responsible for the protection of nerve cells maintaining plasticity and preventing the natural tendancy towards neuron death.
The CREB /CRE system controls gene expression all over the body including those that ensure mitochondrial function directly and indirectly.
As a nice little twist mitochondrial mutations, however small and on their own, may produce someone prone to infection for example.will magnify any abnormality in the CREB/system. Mitochondrial mutations and creb transcriptional abnormalities can interact, turning the party into a full scale riot.
Creb CRE produce proteins which control the binding of interferon alpha to the TFN alphs gene blocking this binding will have a serious effect on. It is possible to block interferon binding of alpha but enhance B producing the innate responses observed in patients with ME and of course lead to a higher level of free interferon alpha that Judy M was talking about
So it's just not getting the XMRV but how it interacts with essential gene systems or not that determines having symptoms the severity of those symptoms and the spread of bodily systems dysregulated.
CREB proteins also control the expression of enzymes essential for the function of the methylation system dysfunction would lead to at least a partial block--The key one is methionine synthase."
Susan,
If viruses can't live without mercury, then it seems like chelating out the mercury would be a cure. I've done it and don't feel any different, although my thyroid labs look better.
I have a classic CFS-style partial methylation block according to the Vitamin Diagnostics test.
But I also believe at this time that you can have either a genetic block or an acquired block. I'm just not sure which one I have. Somewhere in Rich Vank's vast postings, I seem to remember him saying you could get an acquired block from a virus, but heck if I can find it.
If viruses can't live without mercury, then it seems like chelating out the mercury would be a cure. I've done it and don't feel any different, although my thyroid labs look better.
I have a classic CFS-style partial methylation block according to the Vitamin Diagnostics test.
But I also believe at this time that you can have either a genetic block or an acquired block. I'm just not sure which one I have. Somewhere in Rich Vank's vast postings, I seem to remember him saying you could get an acquired block from a virus, but heck if I can find it.
Hi, Caledonia.
In the GD-MCB hypothesis that I've proposed to explain the pathogenesis of CFS involving a partial methylation cycle block, the things that are necessary to bring this about and cause the onset of a case of CFS are the following:
1. A genetic predisposition involving a combination of polymorphisms that have been inherited. Which polymorphisms are necessary has not yet been well-defined, and we need more research in this area. But various lines of evidence lead to the conclusion that there is a genetic component, though it is not yet thoroughly deliniated by research.
2. Exposure to a stressor or a set of stressors that place demands on glutathione and lower it sufficiently to leave vitamin B12 unprotected, setting up a partial block in the methylation cycle. There is a variety of stressors that can contribute to this, including physical, chemical, biological and psychological/emotional stressors, and in many cases I've studied, several of these have impacted the person simultaneously, as in a "perfect storm."
Getting to your question, while I don't know a lot about XMRV yet, I think there are a couple of ways it could figure into this picture. First, since it integrates itself into the human genome, I think it could have a somewhat similar effect as an inherited polymorphism. That is, it could affect the expression of the genes.
Second, I think another possibility would be that it could help to lower the glutathione level, either by a genetic effect on the enzymes that synthesize glutathione, or by a biochemical effect, such as by depleting cysteine, which is the rate-limiting amino acid for making glutathione, or by an immune system effect, such as by depleting glutathione when it deals with the oxidative stress produced by immune cells in combating a viral infection.
These are only speculations at this point, but they are the possibilities I can think of for meshing XMRV with the GD-MCB hypothesis. I look forward to seeing the results of more research on this retrovirus.
Best regards,
Rich
In the GD-MCB hypothesis that I've proposed to explain the pathogenesis of CFS involving a partial methylation cycle block, the things that are necessary to bring this about and cause the onset of a case of CFS are the following:
1. A genetic predisposition involving a combination of polymorphisms that have been inherited. Which polymorphisms are necessary has not yet been well-defined, and we need more research in this area. But various lines of evidence lead to the conclusion that there is a genetic component, though it is not yet thoroughly deliniated by research.
2. Exposure to a stressor or a set of stressors that place demands on glutathione and lower it sufficiently to leave vitamin B12 unprotected, setting up a partial block in the methylation cycle. There is a variety of stressors that can contribute to this, including physical, chemical, biological and psychological/emotional stressors, and in many cases I've studied, several of these have impacted the person simultaneously, as in a "perfect storm."
Getting to your question, while I don't know a lot about XMRV yet, I think there are a couple of ways it could figure into this picture. First, since it integrates itself into the human genome, I think it could have a somewhat similar effect as an inherited polymorphism. That is, it could affect the expression of the genes.
Second, I think another possibility would be that it could help to lower the glutathione level, either by a genetic effect on the enzymes that synthesize glutathione, or by a biochemical effect, such as by depleting cysteine, which is the rate-limiting amino acid for making glutathione, or by an immune system effect, such as by depleting glutathione when it deals with the oxidative stress produced by immune cells in combating a viral infection.
These are only speculations at this point, but they are the possibilities I can think of for meshing XMRV with the GD-MCB hypothesis. I look forward to seeing the results of more research on this retrovirus.
Best regards,
Rich
G
Hi Rich retroviruses are well known gene regulators and thought to provide much of our epigenetic variability.Mulvs in MITO DNA cause misreading very much like polymorphism.CREB/CRE function is essential in the expression of the gene coding for methionine synthase.I have the precise details somewhere
G
This may be useful
Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway*
1. Idrees O. Danishpajooh,
2. Tanima Gudi,
3. Yongchang Chen,
4. Vladimir G. Kharitonov‡,
5. Vijay S. Sharma and
6. Gerry R. Boss
+ Author Affiliations
1.
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0652 and ‡SkyePharma Inc., San Diego, California 92121
Abstract
Many of nitric oxide's biological effects are mediated via NO binding to the iron in heme-containing proteins. Cobalamin (vitamin B12) is structurally similar to heme and is a cofactor for methionine synthase, a key enzyme in folate metabolism. NO inhibits methionine synthase activity in vitro, but data concerning NO binding to cobalamin are controversial. We now show spectroscopically that NO reacts with all three valency states of cobalamin and that NO's inhibition of methionine synthase activity most likely involves its reaction with monovalent cobalamin. By following incorporation of the methyl moiety of [14C]methyltetrahydrofolic acid into protein, we show that NO inhibits methionine synthase activity in vivo, in cultured mammalian cells. The inhibition of methionine synthase activity disrupted carbon flow through the folate pathway as measured by decreased incorporation of [14C]formate into methionine, serine, and purine nucleotides. Homocysteine, but not cysteine, attenuated NO's inhibition of purine synthesis, providing further evidence that NO was acting through methionine synthase inhibition. NO's effect was observed both when NO donors were added to cells and when NO was produced physiologically in co-culture experiments. Treating cells with an NO synthase inhibitor increased formate incorporation into methionine, serine, and purines and methyl-tetrahydrofolate incorporation into protein. Thus, physiological concentrations of NO appear to regulate carbon flow through the folate pathway.
Footnotes
Nitric Oxide Inhibits Methionine Synthase Activity in Vivo and Disrupts Carbon Flow through the Folate Pathway*
1. Idrees O. Danishpajooh,
2. Tanima Gudi,
3. Yongchang Chen,
4. Vladimir G. Kharitonov‡,
5. Vijay S. Sharma and
6. Gerry R. Boss
+ Author Affiliations
1.
From the Department of Medicine, University of California, San Diego, La Jolla, California 92093-0652 and ‡SkyePharma Inc., San Diego, California 92121
Abstract
Many of nitric oxide's biological effects are mediated via NO binding to the iron in heme-containing proteins. Cobalamin (vitamin B12) is structurally similar to heme and is a cofactor for methionine synthase, a key enzyme in folate metabolism. NO inhibits methionine synthase activity in vitro, but data concerning NO binding to cobalamin are controversial. We now show spectroscopically that NO reacts with all three valency states of cobalamin and that NO's inhibition of methionine synthase activity most likely involves its reaction with monovalent cobalamin. By following incorporation of the methyl moiety of [14C]methyltetrahydrofolic acid into protein, we show that NO inhibits methionine synthase activity in vivo, in cultured mammalian cells. The inhibition of methionine synthase activity disrupted carbon flow through the folate pathway as measured by decreased incorporation of [14C]formate into methionine, serine, and purine nucleotides. Homocysteine, but not cysteine, attenuated NO's inhibition of purine synthesis, providing further evidence that NO was acting through methionine synthase inhibition. NO's effect was observed both when NO donors were added to cells and when NO was produced physiologically in co-culture experiments. Treating cells with an NO synthase inhibitor increased formate incorporation into methionine, serine, and purines and methyl-tetrahydrofolate incorporation into protein. Thus, physiological concentrations of NO appear to regulate carbon flow through the folate pathway.
Footnotes
G
NItric oxide and CREB
This paper goes with the first
Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism
1. Masayuki Sasaki*,
2. Mirella Gonzalez-Zulueta*,
3. Hui Huang*,
4. William J. Herring*,
5. Sohyun Ahn,
6. David D. Ginty,
7. Valina L. Dawson*,,, and
8. Ted M. Dawson*,,
+ Author Affiliations
1.
Departments of *Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287
1.
Edited by Louis J. Ignarro, University of California, Los Angeles, CA, and approved May 15, 2000 (received for review January 28, 2000)
Next Section
Abstract
Neuronal nitric oxide (NO) synthase (nNOS) is dynamically regulated in response to a variety of physiologic and pathologic stimuli. Although the dynamic regulation of nNOS is well established, the molecular mechanisms by which such diverse stimuli regulate nNOS expression have not yet been identified. We describe experiments demonstrating that Ca2+ entry through voltage-sensitive Ca2+ channels regulates nNOS expression through alternate promoter usage in cortical neurons and that nNOS exon 2 contains the regulatory sequences that respond to Ca2+. Deletion and mutational analysis of the nNOS exon 2 promoter reveals two critical cAMP/Ca2+ response elements (CREs) that are immediately upstream of the transcription start site. CREB binds to the CREs within the nNOS gene. Mutation of the nNOS CREs as well as blockade of CREB function results in a dramatic loss of nNOS transcription. These findings suggest that nNOS is a Ca2+-regulated gene through the interactions of CREB on the CREs within the nNOS exon 2 promoter and that these interactions are likely to be centrally involved in the regulation of nNOS in response to neuronal injury and activity-dependent plasticity.
Nitric oxide (NO) is an important biological messenger that plays a prominent role in the physiology of the central nervous system. Three isoforms account for NO production and include neuronal NO synthase (nNOS; type I), inducible NO synthase (iNOS; type II), and endothelial NO synthase (eNOS; type III). In the nervous system, nNOS accounts for the majority of the physiologic actions of NO (1, 2). As a diffusible messenger molecule, NO is ideally suited to modulate and regulate synaptic function by acting as a spatial signal (3). Many investigations have shown that nNOS expression is dynamically regulated by both physiological and pathophysiological stimuli; however, the molecular mechanisms controlling the expression of nNOS in response to these stimuli are not known (1, 47).
The structure of the nNOS gene is extremely complicated. Its genomic structure in humans spans more than 240 kilobases, and its expression is potentially regulated by more than nine separate alternative first exons, which splice to a common exon 2 that contains a large 5′ untranslated region (UTR) before the start methionine (8). nNOS expression may be regulated at multiple levels, which could be relevant to a variety of physiologic functions of NO, ranging from a modulator of neuronal plasticity and behavior to a mediator of neuronal cell death (4, 9). To begin to understand how diverse stimuli regulate nNOS expression, we sought to identify the signaling pathways that mediate nNOS expression in neurons. In this study, using primary embryonic cortical neurons, we show that neuronal activity controls nNOS expression through influx of Ca2+ into neurons through L-type voltage-sensitive Ca2+ channels (VSCCs). Furthermore, we find that Ca2+ influx through L-type VSCCs stimulates transcription from the nNOS promoter contained within exon 2 by means of a CREB family transcription factor-dependent mechanism.
This paper goes with the first
Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism
1. Masayuki Sasaki*,
2. Mirella Gonzalez-Zulueta*,
3. Hui Huang*,
4. William J. Herring*,
5. Sohyun Ahn,
6. David D. Ginty,
7. Valina L. Dawson*,,, and
8. Ted M. Dawson*,,
+ Author Affiliations
1.
Departments of *Neurology, Neuroscience, and Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287
1.
Edited by Louis J. Ignarro, University of California, Los Angeles, CA, and approved May 15, 2000 (received for review January 28, 2000)
Next Section
Abstract
Neuronal nitric oxide (NO) synthase (nNOS) is dynamically regulated in response to a variety of physiologic and pathologic stimuli. Although the dynamic regulation of nNOS is well established, the molecular mechanisms by which such diverse stimuli regulate nNOS expression have not yet been identified. We describe experiments demonstrating that Ca2+ entry through voltage-sensitive Ca2+ channels regulates nNOS expression through alternate promoter usage in cortical neurons and that nNOS exon 2 contains the regulatory sequences that respond to Ca2+. Deletion and mutational analysis of the nNOS exon 2 promoter reveals two critical cAMP/Ca2+ response elements (CREs) that are immediately upstream of the transcription start site. CREB binds to the CREs within the nNOS gene. Mutation of the nNOS CREs as well as blockade of CREB function results in a dramatic loss of nNOS transcription. These findings suggest that nNOS is a Ca2+-regulated gene through the interactions of CREB on the CREs within the nNOS exon 2 promoter and that these interactions are likely to be centrally involved in the regulation of nNOS in response to neuronal injury and activity-dependent plasticity.
Nitric oxide (NO) is an important biological messenger that plays a prominent role in the physiology of the central nervous system. Three isoforms account for NO production and include neuronal NO synthase (nNOS; type I), inducible NO synthase (iNOS; type II), and endothelial NO synthase (eNOS; type III). In the nervous system, nNOS accounts for the majority of the physiologic actions of NO (1, 2). As a diffusible messenger molecule, NO is ideally suited to modulate and regulate synaptic function by acting as a spatial signal (3). Many investigations have shown that nNOS expression is dynamically regulated by both physiological and pathophysiological stimuli; however, the molecular mechanisms controlling the expression of nNOS in response to these stimuli are not known (1, 47).
The structure of the nNOS gene is extremely complicated. Its genomic structure in humans spans more than 240 kilobases, and its expression is potentially regulated by more than nine separate alternative first exons, which splice to a common exon 2 that contains a large 5′ untranslated region (UTR) before the start methionine (8). nNOS expression may be regulated at multiple levels, which could be relevant to a variety of physiologic functions of NO, ranging from a modulator of neuronal plasticity and behavior to a mediator of neuronal cell death (4, 9). To begin to understand how diverse stimuli regulate nNOS expression, we sought to identify the signaling pathways that mediate nNOS expression in neurons. In this study, using primary embryonic cortical neurons, we show that neuronal activity controls nNOS expression through influx of Ca2+ into neurons through L-type voltage-sensitive Ca2+ channels (VSCCs). Furthermore, we find that Ca2+ influx through L-type VSCCs stimulates transcription from the nNOS promoter contained within exon 2 by means of a CREB family transcription factor-dependent mechanism.
Oh, I am interested. I am having my autistic children tested for that. I am taking them in the next 1/2 hour to have their blood drawn but might delay to also get them tested for XMRV. I am worried that if they draw the blood tonight (Friday night), the lab will not receive it until Monday and I am not sure if the XMRV test will be effective. They are also getting other tests done as well. Did any of you (that tested for XMRV) get their blood drawn on a Friday? Does it matter?
Nevermind. I just read the instructions and I have to do it on Monday and Thursday. Darn. I could have had it done last night.
Hi, JPV.
I agree with that, too. A partial methylation cycle block, combined with glutathione depletion, will impact the immune system, and particularly will suppress the cell-mediated immune response, which is necessary to combat viral infections. So viral infections can be both a cause and a consequence of a partial methylation cycle block.
Rich
I agree with that, too. A partial methylation cycle block, combined with glutathione depletion, will impact the immune system, and particularly will suppress the cell-mediated immune response, which is necessary to combat viral infections. So viral infections can be both a cause and a consequence of a partial methylation cycle block.
Rich
Hi Rich and Gerwyn, have a look at this:
"...MicroRNAs (miRNAs) regulate gene expression by base pairing with target RNAs, leading to their cleavage in plants or translational inhibition in animals. Now evidence has emerged that in moss, miRNAs can also silence gene expression at the transcriptional level by interacting with DNA, leading to methylation. This discovery broadens the regulatory influence of miRNAs, and the mechanism may also be applicable to other organisms... ... As ABA is a mediator of stress signalling, these results suggest that miRNAs might epigenetically regulate stress-responsive genes.
The physiological regulation of this epigenetic miRNA-induced silencing pathway and the conservation of miRNA pathway components among species suggest that this mechanism might be generally applicable — a topic for future investigation." http://www.signaling-gateway.org/update/updates/201003/nrg2755.html
XMRV DOES integrate near host miRNA sites....
also some viruses encode their own miRNA - this is now thought to be one of the key mechanisms for herpesvirus takeover of the cell machinery. Not sure if XMRV encodes any of those, anyone?
MicroRNAs and their role in viral infection http://www.springerlink.com/content/367k5n024g0x26r6/
"...MicroRNAs (miRNAs) regulate gene expression by base pairing with target RNAs, leading to their cleavage in plants or translational inhibition in animals. Now evidence has emerged that in moss, miRNAs can also silence gene expression at the transcriptional level by interacting with DNA, leading to methylation. This discovery broadens the regulatory influence of miRNAs, and the mechanism may also be applicable to other organisms... ... As ABA is a mediator of stress signalling, these results suggest that miRNAs might epigenetically regulate stress-responsive genes.
The physiological regulation of this epigenetic miRNA-induced silencing pathway and the conservation of miRNA pathway components among species suggest that this mechanism might be generally applicable — a topic for future investigation." http://www.signaling-gateway.org/update/updates/201003/nrg2755.html
XMRV DOES integrate near host miRNA sites....
also some viruses encode their own miRNA - this is now thought to be one of the key mechanisms for herpesvirus takeover of the cell machinery. Not sure if XMRV encodes any of those, anyone?
MicroRNAs and their role in viral infection http://www.springerlink.com/content/367k5n024g0x26r6/
G
natasa do you know exactly where the integration site is is it in the start codon or anywhere upstream of that?
excellent find
excellent find
Don't know.
Would this here provide any answers:
Integration frequency within cancer breakpoints, within common fragile sites, and near miRNAs.
section starting about half page down: http://jvi.asm.org/cgi/content/full/82/20/9964
Would this here provide any answers:
Integration frequency within cancer breakpoints, within common fragile sites, and near miRNAs.
section starting about half page down: http://jvi.asm.org/cgi/content/full/82/20/9964
G
thanks Natasa