As Carl Zimmer recently (and rightly) pointed out at the end of an article on epigenetics, while the concept of being able to alter our epigenetic profiles for therapeutic purposes is a really attractive concept, our current epigenetic therapy options are very, very messy.

Like I said last week:

Lemme give you an example. Lets say we find out that in people with Ke$ha Disease, their GTiM (Good Taste in Music) gene is underexpressed due to hypermethylation of the surrounding DNA. So, YAY! Thats treatable! We have drugs that could fix that, like 5-aza-2′-deoxycytidine!

Um, well, your DNA is also methylated at lots of other positions for very good reasons. Like, keeping mobile and parasitic DNA silent.

Current epigenetic modifying compounds act globally. We cannot simply target the GTiM gene. Sooo… trade Ke$ha Disease for any kind of cancer or potentially another disease altogether?

A non-Ke$ha paper was just published in Nature Oncology that illustrates this catch-22:

Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription

You have a nice, normal, human protein called cMet. cMet does lots of nice, normal, helpful things most of the time, but if your cells screw up and start making a lot more cMet than theyre supposed to, that cell can turn into cancer. cMet is a proto-oncogene.

The cMet gene itself is made up of 21 exons (the transcribed RNA is long, but then all the introns are cut out to make the smaller, final mRNA to be transcribed). In the intron between exon 2 and 3, there is a LINE. This LINE is normally ‘heavily’ methylated, so the LINE is not transcriptionally active…

Until you treat cells with these drugs we use as epigenetic modifiers. Drugs like decitabine and azacytidine we can give some cancer patients to ‘turn on’ their tumor suppressor genes, demethylate the DNA around this LINE, too, allowing it to come back to life.

This would be ‘bad’ in and of itself, as now weve got this formerly paralyzed bit of mobile DNA that is active again.

But in the case of this LINE in cMet, the LINE promoter doesnt just make the LINE RNA. It also makes a weird cMet (cMet that lacks the first two normal exons, and has some LINE sequence in it).

Well crap. Drugs that would hopefully help treat some cancers actually turn on a proto-oncogene… Except, the LINE cMet doesnt really work right, since its not the whole, normal protein.

Punchline FAIL: They dont actually explain whether this is a good thing or a bad thing or what the hell is going on.

:-/

But this paper does illustrate a simple point regarding our current attempts at epigenetic modification:

In this study, we showed the demethylation-dependent induction of an illegimate transcript originating from an intronic L1-ASP located in the cMet gene (L1-cMet). This effect was seen in a variety of cell types including HL-60 myeloid leukaemia cells, an established cellular model for the approved indication of azacytidine and decitabine. In addition, drug-induced activation of illegitimate transcription was also observed at additional retroelement promoters with the potential to produce fusion transcripts between retroelements and neighbouring sequences in HL-60 cells (Weber B, unpublished data). Together, our results thus suggest that the epigenetic activation of illegitimate fusion transcripts may be a relatively common consequence of drug-induced demethylation in human cancer cell lines and, potentially, in patients undergoing demethylation therapy.

While the concept of altering epigenetic profiles is friggen cool, we are currently shooting into the dark.

Remember this the next time a woo-meister tries to sell you some epigenetic BS– Even if what they are pushing works, what is it really doing?

Comments

  1. #1 fnxtr
    June 29, 2010

    So, where would a reasonably brilliant layindividual look for an explanation of how methylation actually works? TYIA.

  2. #2 Brakeman
    June 29, 2010

    So does this mean they might have found the cure for RAP?

  3. #3 Vene
    June 29, 2010

    fnxtr, maybe this will help. Hopefully it’s not too technical.

  4. #4 Fleur
    June 29, 2010

    Alkalinizing your body and getting off the Standard American Diet can prevent and cure almost any cancer!

    Its your life don’t ruin in with the mainstream science and medical B.S. that some arrogant idiot tries to sell you for profit and simply to fight for their dying cause.

    Oh, well what do you expect out of an athiest (though I don’t consider myself to be religious either) they always disregard everything without evidence. The truth is alternative views and things that cannot be proven are always the most effective. Hey, religion won wars for thousands of years (okay, I’m being sarcastic) just like the Chinese have been curing disease for thousands of years with pure healthy diet!

  5. #5 ERV
    June 29, 2010

    Honestly, I havent seen any epigenetics presentations that are acceptable for laypeople (even my own). The super basic one I saw in DC a couple of weeks ago was still too much (okay for grad students and above, though).

    I found this teeny tiny animation at HHMI that is sort of helpful? Just to kinda ‘see’ whats going on?

    Fleur– One of the leading causes of death in China is cancer. Your move, clueless hippie from Ohio.

  6. #6 fnxtr
    June 29, 2010

    Thanks, Vene. And ERV, that was very cool, thank you too.
    (also thanks for not noticing I posted that before reading the quite extensive description on Wikipedia. Not so brilliant after all).

    So, er… can the CpG regions be *anywhere* along the gene, or near the start sequence? What about looking at the chemistry near the CpG region, and using larger, custom-fit molecules to methylate the target… and surely there are other methods besides methylation to block transcription?

    De-methylation looks tough. :-)

  7. #7 Vene
    June 29, 2010

    Trying to ‘alkalinize your body’ is one of the dumber things I’ve heard. It doesn’t even make sense, your body is going to maintain its pH through the retention or removal of salts. This isn’t even mentioning buffers, which resist such change in the first place. Oh, and before I forget, if you do manage to change your pH, it’ll kill you. Your proteins are only able to function at a specific pH range, go outside of that and they degrade. If your proteins don’t work, you die.

  8. #8 Vene
    June 29, 2010

    Oh, something else I forgot to add, I found a contradiction.

    “The truth is alternative views and things that cannot be proven are always the most effective.” and “the Chinese have been curing disease for thousands of years with pure healthy diet!”

    If it’s not something probable, then why is evidence being offered?

  9. #9 Grant
    June 29, 2010

    While not really about how methylation works, nor about epigenetics in cancer, I have a blog post introducing a video about epigenetics and twins that gives some analogies to what it’s all about that I thought might work for non-scientists. Like all analogies, they have their (big and obvious) flaws when pushed, but it might be one starting point:

    http://sciblogs.co.nz/code-for-life/2010/05/17/epigenetics-growing-old-and-identical-twins-becoming-unique/

    The whole thing is intended for non-scientists; it’s way below what someone seriously interested in this would want ;-)

    I hope to write more on this myself at some stage… if I ever find the time…

  10. #10 Buzz
    June 30, 2010

    Hmm, maybe cancer would be a small price to pay to be saved from Ke$ha Disease.

  11. #11 Grant
    July 3, 2010

    If you’re looking for an introduction to epigenetics, PZ Myers has this, which may be more useful than what I previously suggested:

    http://scienceblogs.com/pharyngula/2008/07/epigenetics.php