All posts tagged epigenetics

Could “Junk DNA” Be Causing Chronic Fatigue Syndrome / Myalgic Encephalomyelitis?

Carmen Scheibenbogen

Dr. Scheibenbogen continues to successfully plough new ground

It seems like every time you turn around another part of the genome pops up. It’s amazing how far our knowledge of the human genome has progressed since the Human Genome Project was completed just 15 years ago. Thankfully the small band of researchers involved in chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS) seem to be keeping up with the latest findings.

Dr. Scheibenbogen seems intent on ploughing new ground. First she re-energized the search for autoantibodies in ME/CFS. Then she examined the effectiveness of a promising treatment called immunoadsorption. With her latest study she and her colleagues at Institute for Medical Immunology, Charité-Universitätsmedizin in Berlin became the first in this disease to examine a peculiar part of our genome called long non-coding RNA’s.

Hope for an ME/CFS Autoimmune Subset: A German Researcher Steps Forward

When most people think of RNA they’re probably thinking of the messenger RNA (mRNA) which carries the genetic code from the DNA in the nucleus of our cells to ribosomes. The ribosomes then translate the mRNA into proteins – which then do the work of our cells.

pre mRNA

pre-mRNA -(Wikipedia—httpsupload.wikimedia.orgwikipediacommonsthumbaa4Pre-mRNA-1ysv-tubes)

Not all RNA produces proteins, however. Formerly termed “junk DNA“, non-coding RNA’s – RNA’s which do not encode proteins –  make up a substantial part of our genome.  (They lack the “reading frames” necessary for the process of translation from RNA to protein to begin). Long non-coding RNA’s (lncRNA) are particularly long pieces of RNA (>200 nucleotides long) which do not encode proteins.

While their presence has been known for decades, it wasn’t until the 1990’s that the first hint of the role they play in regulating gene expression and epigenetics  appeared. Research since then has shown that lncRNA’s play an important role modulating the activity of transcription factors which turn the expression of our genes on and off.

Epigenetics –  heritable changes in gene expression that do not involve changes in the underlying DNA sequence – is all the rage now. The ability of infections and other stressors to turn genes on or off via epigenetics presents an intriguing explanation for how an infection could result in ME/CFS. Because lncRNA’s can regulate the epigenetic process, they could provide even more basic insights into how ME/CFS began.

LncRNA’s can also catalyze biological reactions and respond to cellular signals. Their extreme flexibility allows them to interact with proteins, DNA and RNA to affect many physiological processes. One review stated they, “can impact almost all physiological functions.” Another review called them, “a new and crucial layer of biological regulation”.

They’re certainly providing a fresh look at complex diseases. Search for long non-coding RNA’s in PubMed and you’ll get a long list of diseases they may be implicated in. A recent review of the role lncRNA’s may play in cancer called them, “new players in the old battle against cancer”. Some regulate mitochondrial synthesis and energy production.  Pathogens can induce the production of lncRNA’s in humans that then promote viral survival.

It’s become increasing apparent that they can play a role in fundamental developmental processes that can produce chronic disease states. One review called them “arguably the hottest area of RNA research” today.  Still much remains to be learned about the roles they play.

“Remarkable” Finding

The expression signature of very long non‑coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome. Chin‑An Yang1,2,3,4 , Sandra Bauer5, Yu‑Chen Ho3, Franziska Sotzny5, Jan‑Gowth Chang1,3,4† and Carmen Scheibenbogen. Transl Med (2018) 16:231 https://doi.org/10.1186/s12967-018-1600-x

In this study – the first of its kind in ME/CFS – Dr. Scheibenbogen examined the expression of ten very large lncRNAs (> 5 kb) involved in immune regulation, or which influence genes involved in the stress response and/or metabolic and neurologic processes.

The authors were clearly surprised by their findings.  After all, they’d simply taken ten lncRNA’s that they thought, based on findings in other diseases, might play a role in ME/CFS.

In a finding they called “remarkable”, the expression of those ten lncRNA’s was enough to distinguish ME/CFS patients from healthy controls. In fact, the expression of any two of three of these lncRNA’s (NTT, MIAT and EMX2OS) was all that was needed to pick out most ME/CFS patients.

Diagnositic accuracy

The elevated expression of just three lncRNA’s was enough to identify most ME/CFS patients

Then seeking to understand if the chronic illness state present in ME/CFS could be turning these lncRNA’s on by exposing them to biological stressors known to be present in ME/CFS. They found that punishing cell lines with oxidative stress did, in fact, increase the expression of the lncRNA’s. Subjecting the cell lines to a viral stressor also increased expression of one of them. Doing it increased the expression of a gene associated with chronic inflammation and blood vessel dysfunction – two problems that are believed to be present in ME/CFS.

ME/CFS seems to revel in producing findings that baffle researchers and this study was no expression. The enhanced expression of one lncRNA (EMX2OS) was something of a mystery as it is rarely found in the cells (peripheral blood mononuclear cells) they examined. It is, however, increased in brain hypoxia; i.e. low oxygen levels in the brain – which Dr. Shungu’s studies suggest may be present in ME/CFS.

Study Suggests “Bad Energy” is Core Problem in Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)

Finally, the authors noted that it took just three lncRNA’s (NTT, MIAT, and EMX20s) to do what it took Kerr 88 genes and Naviaux 8-13 metabolites to do – differentiate ME/CFS patients from healthy controls. One wonders if Scheibenbogen’s examination of lncRNA’s is getting at some basic components of ME/CFS.

Treatment Implications

No direct treatment implications were mentioned. In the short-term they’re viewed more as providing excellent diagnostic biomarkers. For instance, lncRNA’s are now being used to one of most difficult diagnostic scenarios of all – prostate cancer. They’re now being used in men with high PSA levels and negative biopsy results.

Direct treatments based on lncRNA’s are probably years away but should be noted that lncRNA’s are a very active area of research for a good reason: turning down their expression could turn off basic processes that cause disease. The author of a recent study which found that LncRNA’s play a role regulate fat metabolism reported:

“We are still in the early stages of figuring out how lincRNAs function in human disease, but what used to be considered ‘junk’ in the genome may actually point us towards the jackpot of developing effective therapeutic approaches for cardiometabolic diseases,” Jennie Lin, MD, MTR

This new exploration of ME/CFS patient’s genomes further substantiates the notion that ME/CFS is a disease of immune dysregulation. Given the study’s strong results surely more lncRNA study in ME/CFS is on the way.

 

System Reset? Study Suggests Pro-Inflammatory / Autoimmune Reset Occurred in Chronic Fatigue Syndrome (ME/CFS)

Epigenetics research holds the fascinating possibility of figuring out what shifted at the very beginning of chronic fatigue syndrome (ME/CFS).  For many with ME/CFS a sudden change occurred – some sort of biological reset quickly happened – which never relinquished itself.

epigenetic reset ME/CFS

Something triggered ME/CFS. Could it have been an epigenetic reset?

Finding out what “reset” occurred is what epigenetics is all about.  Epigenetics identifies changes in the expression of our genes that occur after we meetup with biological stressors such as pathogens, drug, toxin or even foods.

Most of our genes that produce proinflammatory cytokines, for instance, have a kind of a lock on them. Removing that lock leaves them free to express themselves and leaves us open to poor health.

Epigenetics explores how the biological challenges we encounter in life can remove those locks (or add to them) resulting in an entirely new genetic landscape – one that could perhaps cause something like ME/CFS.

Many people’s ME/CFS/FM starts with an infection, and viruses can exert major epigenetic changes to our genome.  Herpes simplex virus (the virus Dr. Pridgen is targeting in fibromyalgia) engineers changes to our genome which help the virus avoid destruction and enhance its replication. Those changes include a suppression of our immune system, which can result in an increased risk of cancer.

What goes around comes around, though.  Epigenetic News recently reported that an epigenetic modifying cancer drug was able to return the parts of the immune system that the  herpes simplex virus had disturbed to normal. The drug was able to effectively fill in the immune hole created by the herpes virus by boosting a number of immune factors (IFN-a, IL-8, IL-6, transcription factors, stress response factors). Mouse studies revealed that the drug also reduced reactivation of the virus.

That suggests that some similar drugs now in clinical trials could help in the fight against herpes and other viruses or could perhaps simply return to normal epigenetically modified genes that have suppressed immune functioning.

 “A new class of antivirals based on this study might be useful for patients who are resistant to existing antivirals like acyclovir and ganciclovir….. (or in) viral infections for which there aren’t pharmaceuticals to boost an individual’s immune response.” Dr Kristie

If epigenetics turns out to play the major role in ME/CFS that it does in cancer and other diseases, a cancer drug could someday be in store for ME/CFS treatment.

Epigenetics Study Highlights Immune Alterations in ME/CFS

The epigenetics story begins with gene transcription – the first step in the process of translating our genes into proteins.  Gene expression gets enabled by the removal of methyl groups that block transcription and/or by the addition of methyl groups that stop genes from being expressed.

Malay Trivedi and Lubov Nathanson at Dr. Klimas’s Institute of Neuroimmune Research at Nova Southeastern University recently published the most comprehensive study yet on epigenetics in chronic fatigue syndrome .

Just a few epigenetic studies have been done in ME/CFS and none like this one. For one, the group took advantage of a new breakthrough in genetic testing (an advanced Illumina array) to almost double the number of testing sites (from 450,000 to 850,000 sites). For another, the larger sample size (64 participants from two geographically distant locations) ensured a more comprehensive look at the epigenetic changes in ME/CFS. This allowed the group to produce what they called “consensus hypomethylated sites” they believe could be used in future studies.

The general findings of the study agreed with those from past ME/CFS epigenetic studies. Hypomethylation – the deletion of methyl groups, which make it easier for the genes to be expressed – was the theme, with 98% of differentially methylated sites in ME/CFS hypomethylated compared to controls. (Only 2% were hypermethylated compared to controls.)  The hypomethylation was most prominent in genes associated with immune cell regulation.

The high degree of hypomethylation was intriguing for several reasons. For one, Epstein-Barr Virus – presumably a common trigger in ME/CFS – overwhelmingly triggers hypomethylation and almost no hypermethylation of genes. Hypomethylation is also associated with pro-inflammatory gene expression in autoimmune diseases as well as in cancer promotion.

Multiple Sclerosis Breakthrough

A “global” hypomethylation, for instance, is also found in lupus and rheumatoid arthritis. The hypomethylation of a promoter gene for IL-6 in rheumatoid arthritis causes an overexpression of pro-inflammatory cytokines and other immune factors which ultimately results in joint damage.

Epigenetic changes to the HLA genes may have triggered MS. (HLA Gene Expression – by ZionLion77 – https://en.wikipedia.org/wiki/Human_leukocyte_antigen#/media/File:MHC_expression.svg)

The recently uncovered hypomethylation of an HLA gene in multiple sclerosis (MS) prompted researchers to state that epigenetic changes may even be “caus(ing) the disease”. That bold statement reflected the findings of a recent large study, which indicated that epigenetic changes were directly causing the largest risk factor found yet for MS.

That finding may have implications that go far beyond MS and could conceivably reach ME/CFS/FM.  Since the HLA region of the genome is associated with almost all autoimmune diseases, the authors believe their finding will impact other autoimmune diseases.

(Several years ago Ron Davis pegged the HLA region as a potential study area for ME/CFS. His Stanford Genome Lab has developed new methods of assessing this complex region of our genome, and he and Mike Snyder at Stanford are doing an intensive analysis of that HLA region in ME/CFS.)

Back to Chronic Fatigue Syndrome (ME/CFS)

The highest degree of hypomethylation in a genetic region in ME/CFS occurred in gene promoters associated with natural killer cell functioning, no less – the most consistent finding in ME/CFS.  That suggested that some sort of epigenetic reset – perhaps triggered by an infection – occurred in the NK cells of ME/CFS patients.

With regard to single genes, the authors highlighted the hypomethylation of genes associated with muscle hypotonia (low muscle tone) and cognitive impairment (MED13L), problems with protein synthesis (metabolism), and glucocorticoids (SGK3 gene – inflammation).

It was the immune genes, though, where the hypomethylation really came to the fore. Immune genes that regulate the adaptive immune response (T & B cells) and the production of immunoglobulins were hypomethylated. The authors asserted that those findings were in sync with reports of improvement from Rituximab.

Promoters (MMP14, MAP4K4, MAPK12 and CREB5), which may be activating tumor necrosis factor signaling pathways and thus contributing to the pro-inflammatory problems believed present in ME/CFS, were hypomethylated as well.

A gene (miRNA-148a) that impairs the innate immune response was also hypomethylated. Several of the hypomethylated genes were also found in prior ME/CFS studies.

Then there’s the IL21R gene. The hypomethylation of the IL21R gene promoter in ME/CFS could promote inflammation, autoimmunity, thyroid disease, intestinal inflammation, and others.  IL-21 also plays a critical role in triggering spontaneous experimental autoimmune encephalomyelitis – an animal model of brain inflammation.

Conclusion

IL-SR gene chronic fatigue syndrome

Unleashing the IL2R gene could contribute to inflammation (including neuroinflammation), thyroid disease and autoimmunity

Epigenetics is a relatively new science which is already proving to be a boon to the study of autoimmunity and cancer. Larger studies will be needed in ME/CFS for epigenetics to reach its potential, but the study from Dr. Klimas’s group suggested that, just as in some autoimmune diseases, enhanced hypomethylation may be increasing the expression of genes which promote inflammation and autoimmunity in ME/CFS.

The most encouraging thing about epigenetics is the possibility of reversing the epigenetic changes a pathogen, toxin or drug has caused. Much more study is needed to isolate any epigenetic culprits in ME/CFS, but epigenetic altering drugs are being developed for other diseases. One intriguing drug seeks to reverse the epigenetic changes caused by herpes simplex virus – thus returning the immune system to normal.  Another breakthrough suggests that epigenetic changes may be major drivers of multiple sclerosis.

This is clearly a field to keep an eye on.