Dumb molecular bio question
DNA methylation - important for mismatch repair (template strand is methylated) AND cytosine is methylated to decrease transcription
Histone methylation - only to inactivate transcription --- important in Huntingtons
Is the above correct? Thanks!
Cytosine methylation = gene silencing. Now, this gene silencing can be physiological (genomic imprinting, X chromosome inactivation in females) or pathological (cancer cells).
Now then, what is the deal with mismatch repair and DNA methylation? This brings us back to the pathogenesis of colorectal carcinoma: As I'm sure everyone knows here, one such pathway is very well defined, which is the APC ---> K-ras --> p53 sequence. As mutations accumulate in the mucosa, adenomas, then carcinomas develop. But this is not the whole story. When researchers went back and investigate, they found out that there are certain types of colorectal cancer which did not follow this sequence. These cancers were found in younger patients, and tend to be right-sided (along with other features). And these cancers typically did not have K-ras or p53 mutations. Further analysis revealed that these tumors showed microsatellite instability.
So what is a "microsatellite" then? Like the name suggests, these are small, repeating sequences of DNA, typically found in non-coding regions of the genome. But the issue with colorectal carcinoma is that those microsatellite regions within the coding or promoter regions become mutated (hence the "instability"). And when they become mutated, they decrease the expression of that gene. One example is BAX: microsatellite gets mutated --> Less BAX expression --> Less apoptosis --> Cancer cells can survive.
Then what makes those microsatellite regions become mutated? That brings us back to mismatch repair: As you know, DNA replication is not perfect and there are plenty of chemical and physical mutagens around us. So when these mismatch errors occur, mismatch repair enzymes such as hMLH1 and hMSH2, as their name suggests, find and repair those mismatches. But, if these enzymes are not present, mismatch errors accumulate and create the mutations mentioned above.
We have now come one step closer to the cause: We know that expression of certain key genes can be decreased because of microsatellite instability, and microsatellite instability can be caused by defects in mismatch repair. Then, what causes those defects in mismatch repair? The reason can be (a) inherited and (b) acquired. The most important inherited cause of mismatch repair defect is
Lynch syndrome (HNPCC). These patients have an inherited defect of mismatch repair genes, which creates microsatellite instability, which causes change in gene expression of key enzymes.
Finally, this brings us to (b): Acquired. For reasons not yet clear, some people tend to have epigenetic changes involving these mismatch repair genes. One prominent example is hypermethylation of the promoter regions involved in coding of mismatch repair genes. Because of this, expression of these repair genes get decreased. These promoter regions contain repeating sequences of CpG (CpG islands), so colorectal cancers arising from this initial defect is termed as CpG Island Methylator Phenotype (CIMP) So, whether it is inherited (HNPCC) or acquired (CIMP), decrease in mismatch repair genes result in microsatellite instability, which causes the problems I've mentioned above.
After this long winded discussion, I'll leave it that you're correct in saying that histone methylation is seen in Huntington's. Other epigenetic changes can also be seen involving histones, such as histone acetylation. In fact, there are drugs which target histone deacetylators, such as vorinostat, a drug used in the treatment of cutaneous T-cell lymphoma.
