KLZF KRABs with nine zinc fingers…

Okay, you know how I say with ERVs and disease:

  1. Expression of the ERV protein causes the disease
  2. Expression of the ERV is an effect of the disease (a useful biomarker)
  3. Expression of the ERV is an effect that perpetuates the disease

I just read a paper that exemplifies #3!

Regulation of human endogenous retrovirus-K expression in melanomas by CpG methylation.

So, you know how you have KRABs that bind to ERV DNA, and these KRABs recruit epigenetic machinery that silences the ERVs?

Well, these folks looked in various melanoma cell lines, and looked for a specific ERV we see upregulated in people with advanced/aggressive melanoma: HERV-K. HERV-K is a family of young ERVs. Most of them came about after the human/chimpanzee split, and quite a few of them (50-60) are still pretty complete ERVs (LTRs, gag, pol, and env). Not the solo LTRs and shattered genes that make up most other ERV families. So since these guys are young, they still have the ability to cause trouble.

They looked at a bunch of these HERV-Ks, but focused in on this one on chromosome 7p22, HERV-K-108.

Cells that had lower DNA methylation had higher expression of this HERV. And, when these cells were treated with a compound that screws up DNA methylation, HERV-K-108 expression didnt go up (it did go up in cells that previously didnt express this protein).

So, we can be pretty sure that the reason HERV-K transcripts/proteins in melanoma cells is because their epigenetics, specifically their DNA/histone methylation is screwed up.

But did the activities of this HERV-K start the cancer in the first place?

Probably not:

Demethylation is obviously necessary for the expression of HERV-K. As it is unlikely that HERV-K is able to demethylate its proviruses, the loss of methylation must be the result of genetic changes in the cell, e.g., a loss of DNMT1 activity. Therefore, the activation of HERV-K expression ought to be understood as a secondary event.

But wait! Allowing this ERV to be transcribed isnt just a harmless side-effect/biomarker.

HERV-K encodes two proteins, Rec and Np9. These proteins bind to a KRAB, KLZF, and inhibits KLZFs inhibitory function. In other words, KLZF normally recognizes this ERV sequence and KAP-1 (probably) comes in and epigenetically modifies the DNA. BUT, the viral proteins Rec and Np9 bind up KLZF so it cant see the retroviral DNA, thus KAP-1 doesnt know to go there and silence the DNA, thus you get retroviral transcription.

So if the epigenetic profile of a cell breaks down, transcription of this ERV will be self perpetuating– you make more and more Rec & Np9, thus mess up ERV epigenetics even more.

This causes all kinds of crazy trouble!

The increase in demethylation may enhance expression of HERV-K mRNA as well as Env, Rec and Np9 proteins. As there is preliminary evidence that Rec and Np9 may be involved in tumorigenesis, they may contribute to tumor induction. In addition, the expression of the immunosuppressive Env protein may contribute to tumor progression preventing tumor rejection by the immune system. In this context it is of great interest whether HERV-K proteins are good targets for cancer immunotherapy. Such investigations will help to understand the role of HERV-K proteins, if any, in the development of melanomas.

Probably one of the few cases where having KRABs is a good thing ;)

Oh, and this still doesnt sound like magic, does it? hehehehe!

Comments

  1. #1 mo
    January 26, 2010

    To your magic comments: First you should educate yourself better on what epigenetics is. Your definition is too narrow.

    start by reading this:
    http://www.sciencemag.org/cgi/content/full/286/5439/481

    http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4N3XF1K-3&_user=1634520&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000054038&_version=1&_urlVersion=0&_userid=1634520&md5=cc08ef9ec975b2541dfa31ba5bc40be6

    I really like this research paper:
    “epigenetic programming by maternal behavior”
    http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html

    Epigenetics is not change of gene expression by chromatin mechanisms, but inheritage without mutations. chromatin sometimes plays a role, but only if the modifications are at least inherited by the daughter cells. By this definition, maternal antibodies and prion deseases passed from mother to child are epigenetic.

  2. #2 Vene
    January 26, 2010

    I don’t know, sounds like some sort of voodoo spell to me, but that’s normal for molecular biology (or biochem or genetics or however you want to classify this).

  3. #3 Optimus Primate
    January 26, 2010

    It doesn’t sound like magic; it sounds like the biological equivalent of an explosion! Fascinating.

  4. #4 Optimus Primate
    January 27, 2010

    Mo, have you taken the time to read this post?

  5. #5 TotallyUncool
    January 28, 2010

    That sounds kind of like one of those impossible prison breaks that comic book villains are always pulling off:
    “Bad news, Boy Wonder! HERV-K-108 has broken out of prison!”
    “Rampaging retroviruses, Batman! How did that happen!?”
    “He waited until one of his toenails grew so long that the tip was outside of the epigenetic force-field that kept him immobilized!”
    “Just one toenail!? But what could he do with that!?”
    “With HERV-K-108′s super escape powers, that was all he needed! He used it to shut down the epigenetic force field, and now he’s expressing himself all over the place!”

    My first guess would be that HERV-K evolved that trick as a strategy for breaking free and expressing itself on those occasions when the epigenitic locks that keep it confined fail. Or maybe it was a strategy for preventing the epigenetic lockdown from happening in the first place. A nasty trick, whatever it is…

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