Paper: long non-coding RNA in ME/CFS

[boolybooly]

Dr Fluks kindly posted this to an email group, I thought I better pass it on. Shows a signature in long non coding / functional RNA expression of sequences previously associated with immune processes.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1600-x

The expression signature of very long non-coding RNA in myalgic encephalomyelitis/chronic fatigue syndrome.

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease with huge social-economic impact. It has been suggested that immune dysregulation, nitrooxidative stress, and metabolic impairment might contribute to disease pathogenesis. However, the etiology of ME/CFS remains largely unclear, and diagnostic/prognostic disease markers are lacking. Several long noncoding RNAs (lncRNA, > 200 bp) have been reported to play roles in immunological diseases or in stress responses.

Methods
In our study, we examined the expression signature of 10 very long lncRNAs (> 5 kb, CR933609, His-RNA, AK124742, GNAS1-AS, EmX2OS, MIAT, TUG1, NEAT1, MALAT1, NTT) in the peripheral blood mononuclear cells of 44 ME/CFS patients.

Results
LncRNAs NTT, MIAT and EmX2OS levels were found to be significantly elevated in ME/CFS patients as compared with healthy controls. Furthermore, NTT and EmX2OS levels increased with disease severity. Stimulation of human monocytic cell line THP-1 and glioma cell line KALS1 with H2O2 (oxidative stress) and poly (I:C) (double strand RNA, representing viral activation) increased the expression levels of NTT and MIAT.

Conclusions
Our study revealed a ME/CFS-associated very long lncRNA expression signature, which might reflect the regulatory response in ME/CFS patients to oxidative stress, chronic viral infection and hypoxemia. Further investigations need to be done to uncover the functions and potential diagnostic value of these lncRNAs in ME/CFS.

 

[Belbyr]

If anyone can break this down into something easily understandable, I'm all ears...

 

[boolybooly]

OK I can repost the following, which is my take on it posted elsewhere.

I am still catching up myself; basically they studied white blood cells and found a type of molecule was expressed more in ME/CFS than in healthy controls.

(NTT, MIAT and EmX2OS.) (nature on MIAT)

So it is indicative of a difference in ME and the nature of the white cell and the molecules concerned implies it is related to an immunological change.

The molecules are three long chain RNAs. We dont know a lot about them, but they are often expressed in conjunction with other pathology for reasons we dont understand yet. e.g. NTT - virus responses, MIAT - myocardial infarction and prostate cancers and EmX2OS - present in normal endometrium but absent in endometrial cancer. As far as I know it does not mean PWME are any more likely to get these other illnesses, it just means the body's response to the conditions creating serious medical conditions in other tissues is as profound at a molecular level as the response to ME in the blood. We just dont know what this means yet but it potentially shows how serious ME is.

These molecules are large and made of RNA which normally encodes genes copied from DNA (as messenger RNA) and short segments of transfer RNA also help decode genes to build proteins in the ribosome. But a molecule is a molecule and sometimes RNA can be used structurally or like an enzyme by biology and evolution which does not mind so much how we classify molecules, as long as it works. In the case of these long chain RNAs we are not sure how they are helping but they do not code for genes and they are far too big to be transfer RNAs... probably... at least not in the conventional sense! So they are a bit of a mystery for now.

That is about as far as I have got with it, one to keep our eyes on but not worth worrying about until more facts are in.

 

[Murph]

Full text is here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098652/

Seems long, non-coding RNA (LncRNA) can turn genes on and off. It is a relatively new discovery in disease.They're not too sure what role it plays in disease, but they keep finding it on the scene in a suspicious way. They're mostly just cataloguing the fact that something is going on with these, certainly not finding a cure right now.

"Emerging roles of very large (> 5 kb) lncRNAs in immune regulation and disease processes are being discovered."

The role of LncRNA is still a bit ?

LncRNAs are key regulators of chromatin state, which show great capacity to interact with more than one protein in different context, and fine-tune the cellular response [8]. It has been reported that lncRNAs play essential roles in complex diseases, such as cancer and autoimmune diseases [9–11]. Although more and more lncRNAs are being discovered, most of their functions and mechanisms of actions are still unknown, especially for the very large lncRNAs that have sizes of more than 5000 nucleotides. We had particular interests in ten very large lncRNAs (> 5 kb), which have been either reported to be involved in immune regulation, or are located close to genes regulating stress response, metabolic and neurologic processes, thus potentially playing a role in ME/CFS.


Here's a graphic showing healthy controls and patients with high and low functioning (as measured by Bell scores) Only three of the RNAs are significantly upregulated in mecfs: NTT, MIAT, EM2XOS.

Some details on the ten lncRNAs. I underlined the ones that showed significant difference in MECFS.

The ten lncRNAs are NTT (17 kb), NEAT1 (23 kb), MALAT1 (7.5 kb), TUG1 (7.1 kb), MIAT (9.9 kb), His-1 RNA (8.4 kb), GNAS1-AS (8.9 kb), EMX2OS (7.3 kb), CR933609 (8.8 kb) and AK124742 (6 kb). NTT was first described in activated T cells, while NEAT1 has been reported to be involved in human lupus and in immune response to viral infections [11–13]. MALAT1 has been found to regulate LPS-induced inflammatory response, and TUG1 is involved in the regulation of cold-induced oxidative stress and inflammation [14–16]. As for MIAT, it is known to play roles in a variety of disease processes, including myocardial infarction, microvascular dysfunction, schizophrenia, and neurogenic commitment [17, 18].

His-1 RNA has been implicated in leukemogenesis, and GNAS1-AS is an imprinted anti-sense transcript at the locus of GNAS1, encoding neuroendocrine secretory protein [19, 20]. According to the lncrnadb database, EMX2OS is an opposite strand transcript of EMX2 gene, and possibly regulates EMX2 [21]. Both EMX2OS and EMX2 RNAs have been detected in the central nervous system (CNS) tissues [22]. For CR933609, we have previously identified its role in protecting INO80D from downregulation by miRNA-5096 [23]. Since INO80D is a main component of the chromatin re-modeler INO80 complex which regulates cell glycolytic and respiratory capacities, CR933609 could be involved in maintaining metabolic stability [24]. Finally, AK124742 has been reported to be an antisense RNA to the gene PSMD6, which encodes components of proteasome, involving antigen presentation by MHC class I and DNA damage repair [25, 26].

They mention these RNAs as a possible biomarker with a decent but not spectacular ability to discriminate cases from controls, pending further studies:

Using expression of any two of these three lncRNAs (NTT, MIAT and EMX2OS) in discriminating ME/CFS from healthy had an AUC of 0.82 on ROC curve, suggesting a potential diagnostic value of these lncRNAs for ME/CFS....

... However, we do not know yet whether this lncRNA profile found in our study is specific for ME/CFS or can be found in other diseases involving immune dysregulation or oxidative stress, such as autoimmune diseases and cancer. It has been reported that MIAT levels could be upregulated in high glucose conditions and in lung cancer, and NTT expressions might be found in processes involving T cell activation [12, 17, 29]. Further comparing the PBMC expression signature of NTT, MIAT, and EMX2OS in ME/CFS with patients suffering from chronic fatigue due to autoimmune diseases or cancer is important to assess the lncRNA test specificity in diagnosing ME/CFS.

So this is mostly a discovery of a molecular feature of this disease, that affirms its physical reality and for now does not suggest any treatment. It is more just to bank the discovery away in case oncology researchers hit upon some meaning or use of LncRNA.