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Role of EZH2 in ME/ CFS and POTS

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Hi, I have been a silent reader of this forum for many years. During the past couple of months, I often had to think about a study from Australia. There, it is said, that POTS (at least in a subgroup) is caused by an epigenetic malfunction of the NE-Transporter. This epigenetic malfunction can be removed in vitro by using an EZH2 inhibitor (GSK126). The EZH2 expression in POTS patients was about 70% higher compared to the healthy controls. The first EZH2 inhibitor (Tazemetostat) is available since this year for certain types of cancer.
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.315654

In the consequence, I did some research, whether an overexpression of EZH2, could not only explain POTS, but other findings of ME/ CFS as well. I did find some very interesting points (at least in my opinion):

First of all, EZH2 is temporally upregulated during certain virus infections (including EBV):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262262/

In 2017, it was stated, that EZH2 inhibitors could, in the future, act as broadband antivirals:
https://mbio.asm.org/content/8/4/e01141-17

EZH2 upregulation leads to a pro-inflammatory state and mediates inflammation (including intestinal and mediates spinal neuroinflammation and neuropathic pain (in rats)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410968/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547712/
https://www.oarsijournal.com/article/S1063-4584(18)30443-6/fulltext

The absence of Ezh2 leads to reduced cytokine secretion and suppresses macrophage- dependent disease development. EZH2 inhibitors could even attenuate sepsis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940273/
https://pubmed.ncbi.nlm.nih.gov/31518916/

Steroidogenic Differentiation in the Adrenal Cortex is programmed by EZH2
https://pubmed.ncbi.nlm.nih.gov/30541888/

EZH2 overexpression leads to allergic inflammation and mast cell degradation (Mast Cell Activation Syndrome)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542604/

Very interesting to me is the role of EZH2 in the circadian clock function, as delayed sleep- phase-circle is a problem, many of us are facing.
https://www.jbc.org/content/281/30/21209.full

Ezh2 Regulates Differentiation and Function of Natural Killer Cells Through Histone Methyltransferase Activity
https://pubmed.ncbi.nlm.nih.gov/26668377/

Another interesting point to me is that EZH2 is located on chromosome 7. Other disorders associated with this chromosome are Ehlers-Danlos-Syndrome and Marfan-Syndrome. With both, there is a huge overlap with ME/ CFS.
So, I would find it very interesting if these findings from Australia could be replicated, not only in POTS, but in ME patients as well.
Given the fact that temporary EZH2 upregulation is normal in certain infections (e.g. EBV) etc., the question is (in case these findings can be replicated), why is EZH2 trapped at such a high level in patients? Probably, a gene that is faulty in certain connective tissue diseases, is responsible for down-regulation after the event in healthy persons?

Btw. some of the supplements, many of us are taking act as an EZH2 inhibitor (at least in vitro), including Omega3, broccoli. quercetin, curcumin.
https://europepmc.org/article/pmc/pmc4552355

In vivo, EZH2 down-regulation can be achieved by melatonin (concerning cancer in this study)
https://pubmed.ncbi.nlm.nih.gov/27121240/

I would be very interested in your opinion about this. Maybe, some of you have experiences with certain herbals or melatonin concerning general inflammation.

Greetings from Germany

Philipp
 

bread.

Senior Member
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Hi, I have been a silent reader of this forum for many years. During the past couple of months, I often had to think about a study from Australia. There, it is said, that POTS (at least in a subgroup) is caused by an epigenetic malfunction of the NE-Transporter. This epigenetic malfunction can be removed in vitro by using an EZH2 inhibitor (GSK126). The EZH2 expression in POTS patients was about 70% higher compared to the healthy controls. The first EZH2 inhibitor (Tazemetostat) is available since this year for certain types of cancer.
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.315654

In the consequence, I did some research, whether an overexpression of EZH2, could not only explain POTS, but other findings of ME/ CFS as well. I did find some very interesting points (at least in my opinion):

First of all, EZH2 is temporally upregulated during certain virus infections (including EBV):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262262/

In 2017, it was stated, that EZH2 inhibitors could, in the future, act as broadband antivirals:
https://mbio.asm.org/content/8/4/e01141-17

EZH2 upregulation leads to a pro-inflammatory state and mediates inflammation (including intestinal and mediates spinal neuroinflammation and neuropathic pain (in rats)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410968/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547712/
https://www.oarsijournal.com/article/S1063-4584(18)30443-6/fulltext

The absence of Ezh2 leads to reduced cytokine secretion and suppresses macrophage- dependent disease development. EZH2 inhibitors could even attenuate sepsis.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940273/
https://pubmed.ncbi.nlm.nih.gov/31518916/

Steroidogenic Differentiation in the Adrenal Cortex is programmed by EZH2
https://pubmed.ncbi.nlm.nih.gov/30541888/

EZH2 overexpression leads to allergic inflammation and mast cell degradation (Mast Cell Activation Syndrome)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542604/

Very interesting to me is the role of EZH2 in the circadian clock function, as delayed sleep- phase-circle is a problem, many of us are facing.
https://www.jbc.org/content/281/30/21209.full

Ezh2 Regulates Differentiation and Function of Natural Killer Cells Through Histone Methyltransferase Activity
https://pubmed.ncbi.nlm.nih.gov/26668377/

Another interesting point to me is that EZH2 is located on chromosome 7. Other disorders associated with this chromosome are Ehlers-Danlos-Syndrome and Marfan-Syndrome. With both, there is a huge overlap with ME/ CFS.
So, I would find it very interesting if these findings from Australia could be replicated, not only in POTS, but in ME patients as well.
Given the fact that temporary EZH2 upregulation is normal in certain infections (e.g. EBV) etc., the question is (in case these findings can be replicated), why is EZH2 trapped at such a high level in patients? Probably, a gene that is faulty in certain connective tissue diseases, is responsible for down-regulation after the event in healthy persons?

Btw. some of the supplements, many of us are taking act as an EZH2 inhibitor (at least in vitro), including Omega3, broccoli. quercetin, curcumin.
https://europepmc.org/article/pmc/pmc4552355

In vivo, EZH2 down-regulation can be achieved by melatonin (concerning cancer in this study)
https://pubmed.ncbi.nlm.nih.gov/27121240/

I would be very interested in your opinion about this. Maybe, some of you have experiences with certain herbals or melatonin concerning general inflammation.

Greetings from Germany

Philipp

Hello Phillip, I have already looked at the topic, I have very strong pots, even sitting in bed. I think you should also post your post on s4me and reddit. I tried to forward the post directly to Prusty and Janet Dafoe.

Greeting,
 
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Hello Phillip, I have already looked at the topic, I have very strong pots, even sitting in bed. I think you should also post your post on s4me and reddit. I tried to forward the post directly to Prusty and Janet Dafoe.

Greeting,
Okay, I am going to do it! Thank you for your help!
 
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Learner1

Senior Member
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@Philipp05 Many of us have autoimmune POTS caused by adrenergic and muscarinic antibodies, typically triggered by a herpes family virus like HHV6. How does your theory relate to this, please?
 

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I do have these antibodies as well, including the „new“ ones against AT1R and ETAR. Interestingly, these antibodies occur in Systemic Scleroderma as well. It is an autoimmune disease, against which Rituximab and Cyclophosphamide do not (or very little) help. In Systemic Scleroderma, EZH2 is overexpressed as well and EZH2 inhibitors are being discussed as a potential treatment.
https://sclerodermanews.com/2019/02...er-way-of-treating-scleroderma-study-reports/
 

bread.

Senior Member
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@Philipp05 Many of us have autoimmune POTS caused by adrenergic and muscarinic antibodies, typically triggered by a herpes family virus like HHV6. How does your theory relate to this, please?
That is just a plain incorrect statement, all of these antibodies are found in many many different diseases.
 

Sushi

Moderation Resource Albuquerque
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There, it is said, that POTS (at least in a subgroup) is caused by an epigenetic malfunction of the NE-Transporter.
The Autonomic department at Vanderbilt University was studying this many years ago—I don’t know if it was published but it was a hot topic among patients about 12 years ago.
 
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The Autonomic department at Vanderbilt University was studying this many years ago—I don’t know if it was published but it was a hot topic among patients about 12 years ago.
I know that the Monash University started to look at the NE-Transporter many years ago after a genetic alteration was found in one specific family. This is a follow-up study identifying a potential treatment.