Human endogenous retroviruses again

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Human endogenous retroviruses again

Postby TwistedHelix » Thu Mar 06, 2008 6:51 am

I could SWEAR I had posted this last night, but right at this moment it's probably mystifying readers of a forum about using mayonnaise during foreplay. I'll try and remember what I said: something about human endogenous retroviruses beings sequences of viral DNA which have become incorporated into our own genome. Up to this point I had heard that only very few were capable of producing a viable viral particle, but this abstract talks about a " substantial fraction" which can reinfect the host, reinsert their DNA at random points, and alter gene expression. Not only that, but they can do this in response to stresses caused by infections, injury or environment, all of which have been posited as triggers for MS, (but let's face it: what hasn't?):

008 Feb 28 [Epub ahead of print]
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ENDOGENOUS RETROVIRUSES IN SYSTEMIC RESPONSE TO STRESS SIGNALS.

Cho K, Lee YK, Greenhalgh DG.

Burn Research, Shriners Hospitals for Children Northern California, and Department of Surgery, University of California, Davis, Sacramento, California.

Infection of germline cells with retroviruses initiates permanent proviral colonization of the germline genome. The germline-integrated proviruses, called endogenous retroviruses (ERVs), are inherited to offspring in a mendelian order and belong to the transposable element family. Endogenous retroviruses and other long terminal repeat retroelements constitute ~8% and ~10% of the human and mouse genomes, respectively. It is likely that each individual has a distinct genomic ERV profile. Recent studies have revealed that a substantial fraction of ERVs retains the coding potentials necessary for virion assembly and replication. There are several layers of potential mechanisms controlling ERV expression: intracellular transcription environment (e.g., transcription factor pool, splicing machinery, hormones), epigenetic status of the genome (e.g., proviral methylation, histone acetylation), profile of transcription regulatory elements on each ERV's promoter, and a range of stress signals (e.g., injury, infection, environment). Endogenous retroviruses may exert pathophysiologic effects by infection followed by random reintegration into the genome, by their gene products (e.g., envelope, superantigen), and by altering the expression of neighboring genes. Several studies have provided evidence that ERVs are associated with a range of pathogenic processes involving multiple sclerosis, systemic lupus erythematosus, breast cancer, and the response to burn injury. For instance, the proinflammatory properties of the human ERV-W envelope protein play a central role in demyelination of oligodendrocytes. As reviewed in this article, recent advances in ERV biology and mammalian genomics suggest that ERVs may have a profound influence on various pathogenic processes including the response to injury and infection. Understanding the roles of ERVs in the pathogenesis of injury and infection will broaden insights into the underlying mechanisms of systemic immune disorder and organ failure in these patients.

PMID: 18317406 [PubMed -
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Postby BioDocFL » Thu Mar 06, 2008 10:14 pm

There are ~50,000 LINE1 sequences throughout the human genome. LINE1 sequences originate from reverse transcriptases from retroviruses. An estimated 60 of the copies code for fully functional reverse transcriptases.
So, if in a heat shock response, one of the functional LINE sequences gets transcribed by opening up of its gene due to chromatin disruption, or epigenetic changes, the functional LINE RNA transcript could get translated into a protein by the ribosome. What is the first thing that a LINE reverse transcriptase could pick up and reverse transcribe? How about Alu sequences which are clustered around the ribosome for some unknown reason. See:
M. Dewannieux, C. Esnault, T. Heidmann ‘LINE-mediated retrotransposition of marked Alu sequences’ Nature Genetics (2003) 35:41-48.
They found that Alu RNA sequences are anchored at the ribosome and are 300x more likely to be transcribed than any other RNA transcripts by a new reverse transcriptase.
So now you have Alu RNA being reverse transcribed into Alu DNA. See also:
A.N. Carnell, J.I. Goodman ‘The long (LINEs) and the short (SINEs) of it: altered methylation as a precursor to toxicity’ Toxicological Sciences (2003) 75:229-235.
Alu sequences are highly enriched in GC sequences (9x compared to the rest of the genome). And so any new Alu DNA should be heavily methylated, otherwise it will appear as if it is invading bacterial DNA that doesn't have methylation of cytosines. But, as I hypothesize, in the heat shock response that led to the expression of previously sequestered LINE genes, there is also over-expression of polyamine synthesis genes due to some chromatin disruption, leading to a reduction of S-adenosylmethionine needed for DNA methylation, there would no longer be sufficient S-adenosylmethionine around to make sure that the new Alu DNA sequences get methylated properly. So now hypomethylated Alu DNA can be released and encounter the immune system which interprets it as foreign due to the improper methylation. Does this happen? See:
J.Z. Li, C.R. Steinman ‘Plasma DNA in systemic lupus erythematosus. Characterization of cloned base sequences’ Arthritis Rheum. (1989) 6:726-33.
Because Alu sequences are GC rich, they can also go into Z-DNA conformations more readily and polyamines, particularly spermine (which I hypothesize is being over-expressed), can stabilize Z-DNA. So the Alu being encountered by the immune system could also be stabilized as Z-DNA, which is usually only transiently seen in cells. I don't have a reference handy but do a search on Z-DNA and lupus and you will see that Z-DNA is a prominent target of lupus auto-antibodies.
I am referenceing lupus but I have stated before that I believe lupus and MS are similar, but occurring primarily in different tissues with different accesibility by the immune system and therefore different appearances. Hope this is clear. It is stuff I have stated before.
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Postby dignan » Thu Mar 06, 2008 10:54 pm

Let me just do a quick 8 year visit to university, then that post will be clear as a bell! Anyhow, it was still interesting, thanks for the explanation.
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Postby BioDocFL » Fri Mar 07, 2008 8:05 am

It was a good bit of detail. At least I didn't write it in Latin (since I don't know Latin).
It is complicated stuff but I have been seeing patterns in it. Alu sequences are about 80-410 bases long. This is similar length to the DNA framentation seen in apoptosis, so I am thinking some of what is interpreted as apoptosis fragmentation in auto-immune diseases could actually be some reverse transcription of Alu RNAs which have been around the ribosome as potential alarm signals. And 80-410 bases long is enough to bind histones, even form nucleosome-like complexes since nucleosomes have 8 histones and 145 base pairs. This could then draw histones in as auto-antigenic targets since they are then associated with the auto-antigenic DNA (hypomethylated reverse transcribed Alu as an example). Again, relative to lupus. But I see lupus as being an auto-immune reaction in tissues where the auto-antigens are more accessible. MS is an auto-immune reaction in less-accessible sites and so other consequences come to the fore first, like cell-death and problems with myelination.
There is a lot of hypothesis on my part in this but it seems to explain a lot.
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Postby gwa » Fri Mar 07, 2008 8:39 am

Biodoc,

There has been a lot of research published lately referring to proteins being the culprits in different autoimmune diseases. Do you have any thoughts on the subject.

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