5-azacytidine has been in the public eye for quite a while now, and it’s been widely known as a powerful demethylating agent in clinical trials for cancer. So you can imagine our surprise when a new publication in Epigenetics caught 5-azacytidine also living a secret life of reorganizing histone modifications…lots of them.
Researchers from UC Davis, using a series of ChIP-chip and MeDIP experiments paired with NimbleGen promoter arrays, studied how 5-azacytidine (Vidaza®) effects global gene expression and histone modifications (H3K9me3 and H3K27me3). Their work uncovered some surprising results:
- They found over 1,400 gene expression changes from 5-azacytidine treatment. No shock there, but it was new. It seems that other global gene expression studies have mostly used 5-aza-2’-deoxycytidine (decitabine), which doesn’t incorporate into both RNA and DNA like 5-azacytidine does, and probably behaves differently.
- Most genes with expression changes, were not methylated before treatment, as you might assume, suggesting secondary effects from 5-azacytidine are involved in gene expression.
- 5-azacytidine had major effects on histone methylation. About 90% of promoters with H3K9me3 or H3K27me3 histone marks lost them after 5-azacytidine treatment, even though both marks were actually enriched overall in the rest of the genome.
- Most gene expression changes were not the result of de-repression, pointing out that 5-azacytidine seems to affect genes within active chromatin domains.
On second thought, considering this quote from our article on Epigenetic Drugs last November, maybe these results aren’t such a surprise. “There’s a clear understanding of how Vidaza demethylates DNA,” says Jay Backstrom, Vice President of Clinical Development for MDS at Celgene. “But at the end of the day, how Vidaza® exerts its clinical benefit and to what extent incorporation into RNA or downstream effects plays a role are still areas of active research.”
At the risk of practicing sensationalistic journalism; we clearly haven’t learned all there is to know about 5-azacytidine just yet!
Get the latest scoop on how 5-azacytidine works at Epigenetics, April 2010.