Hey, you guys remember a while back, when Casey 'Tits' Luskin about peed his pants because 'ERVS AR BE FUNKSHUNAL!!'
Except, this is really another case of Creationists not knowing the difference between an ERV, solo LTRs, and random wayward ERV genes.
Well, like I have said a million times on this blog, these solo LTRs, like all endogenous retroviral bits are not usually good things, CAUSE THEY CAUSE CANCER.
Finally, these two scientific concepts have been combined into one exciting Biblical adventure!
Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma--
Mammalian genomes contain many repetitive elements, including long terminal repeats (LTRs), which have long been suspected to have a role in tumorigenesis. Here we present evidence that aberrant LTR activation contributes to lineage-inappropriate gene expression in transformed human cells and that such gene expression is central for tumor cell survival. We show that B cell-derived Hodgkin's lymphoma cells depend on the activity of the non-B, myeloid-specific proto-oncogene colony-stimulating factor 1 receptor (CSF1R). In these cells, CSF1R transcription initiates at an aberrantly activated endogenous LTR of the MaLR family (THE1B). Derepression of the THE1 subfamily of MaLR LTRs is widespread in the genome of Hodgkin's lymphoma cells and is associated with impaired epigenetic control due to loss of expression of the corepressor CBFA2T3. Furthermore, we detect LTR-driven CSF1R transcripts in anaplastic large cell lymphoma, in which CSF1R is known to be expressed aberrantly. We conclude that LTR derepression is involved in the pathogenesis of human lymphomas, a finding that might have diagnostic, prognostic and therapeutic implications.
Punchline-- Loss of CpG methylation (doesnt that sound magical?) leads to disregulation of an ERV LTR, which then acts as a promoter for a protein that cell shouldnt make, leading to a B-cell cancer.
So here is what they did in this paper: They knew that in Hodgkins lymphoma, B-cells are expressing proteins they arent supposed to express, and not expressing proteins they are supposed to express. Even outside of the whole 'cancer' thing, these B-cells aint right.
One wrong thing they express is CSF1R, normally found on macrophages. It helps this cancer 'survive'.
Why is this receptor being expressed in the wrong cell? Its normal expression is a tightly controlled series of events that require a transcription factor, PU.1. But these cells dont have any PU.1. And, CSFR1 is not being made via an alternative promoter used in trophoblasts either.
So how is this CSFR1 being made? Apparently, transcription of this receptor is being driven by an alternative alternative promoter-- an ERV LTR. It just needs some stock-standard transcription factors like NF-ÎºB, AP-1 and Sp1.
Okay, even if this LTR uses available transcription factors, it shouldnt matter. LTRs are epigenetically silenced. The transcription factors should NOT have access to these promoters, whether they can bind or not. Hell, this whole region should be silenced, because B-cells dont normally express this gene. Well, something has gone wrong in these cells epigenetic profile-- a whole family of ERV LTRs are not appropriately silenced. Its just this one not being silenced causes Hodgkins lymphoma.
DARE YOU ASK WHY?
BEHOLD THE ALMIGHTY POWER OF THE UNIVERSE MANIFESTED IN EPIGENETICS!!
... we identified an HRS cell-specific loss of the ETO family member CBFA2T3 (also called MTG16 or ETO2), which acts as a transcriptional repressor via interaction with HDACs and corepressors such as N-CoR and SIN3 (ref. 25). In contrast to other B cell-derived cell types, all of which expressed CBFA2T3 (Fig. 4c and Supplementary Fig. 7), nearly all HRS cell lines lacked CBFA2T3 mRNA and protein expression (Fig. 4c).
I think that is going to be the plot for the next animated Disney movie. So magical.
You need a transcription repressor, CBFA2T3, to silence this family of ERV LTRs. Lose CBFA2T3, lose epigenetic silencing, start making proteins you arent supposed to make, cancer. You can do the same thing to cells by treating them with chemicals that modify their epigenetic profile.
In summary, our work reveals the first example to our knowledge of endogenous repeat element-driven activation of a proto-oncogene in human malignancies. These data strongly suggest that the loss of epigenetic control and the subsequent transcriptional activation of repeat elements have an important role in the malignant transformation of human cells.
Speaking of cancer:
This is like the devil burying bones to test our faiths. Except that in this case he's burying the nuts and bolts of junk DNA that other bits of our DNA needs to keep the junk junky. Originally that junk got put there via some virus. You know who else puts stuff in our DNA with viruses? Scientists! And as we know Science is the work of the Devil, so clearly all the pieces are falling into place. Regardless that some ERVs are stuck in our genomes from before our split with Chimpanzees, clearly they all just got added after the fall of man.
I have to remind myself that if I were to ever write up my 'research' it'd likely be just as incomprehensible to outsiders.
"CpG methylation" immediately makes me think "cyclopentadienyl" but leave me scratching my head as to what sorta metal "G" could be.
incomprehensible to outsiders..."CpG methylation"
Don't get too bummed out - CpG is a name even us biologists scratch our heads at. CpG methylation refers to a modification our bodies make to our DNA - we add a methyl group to our DNA anywhere the DNA code reads CG (A,T,C,G being the four "letters" of our DNA). The purpose of this ranges from identification of self verses foreign DNA (bacterial DNA is usually not CpG methylated) and for identifying the new strand of DNA when cells replicate (it won't be methylated immediate).
As to why its called CpG, the DNA bases are connected by phosphate groups - all of them, not just C-G bonds. As to why the discoverers called it CpG instead of CG is a mystery to all biologists.