DNA methylation has long been considered a key epigenetic driver in transcription, but lately histone modifications have been stealing some of the regulatory thunder. Histone mods like H3K4me3, H3K27me3 and H4 acetylation have shown researchers they’re not afraid to get conrolling when it comes to miRNA transcription either. Researchers from the Institute of Genetics and Biophysics in Naples, Italy set out to show how mutated DNA methyltransferase 3B (DNMT3B) changed miRNA patterns, which they did, it just turned out to work through a different mechanism than they expected.
Immunodeficiency, Centomeric region instability, Facial anomaly (ICF) syndrome is a rare recessive DNA methyltransferase deficiency disease, that leads to reduced global genomic methylation thanks in part to mutations in the DNMT3B gene. The Italian scientists began checking out epigentics in ICF by cranking out miRNA microarray and qRT-PCR experiments that found 89 differentially expressed miRNAs in their ICF samples. They initially thought that those miRNA expression changes were caused by hypomethylation of CpG islands in the miRNA genes. A pretty reasonable assumption considering that a mutated DNMT3B wouldn’t be able to help keep things methylated. But then they found the M. Night Shayamalan-style twist: When they looked at CpGs associated with those miRNAs with bisufite sequencing, they didn’t a see significant decrease in DNA methylation.
The team next used ChIP assays to see if histone modifications might be the answer, and found altered H3K4me3, H3K27me3 and H4 acetylation around the five miRNA clusters that they checked. Although it’s unclear whether this data applies to situations outside of the ICF model, here are some of the conclusions they draw about DNMT3B regulation of miRNAs:
- DNMT3B is able to block transcription independent of methylation activity, apparently by changing histone mods.
- Mutant DNMT3B may interfere with the ability of chromatin remodeling complexes to bind or set chromatin states.
- miRNA gene cluster expression gets regulated, much like protein-coding genes, by DNMT3B controlled chromatin structure.
So, symptoms of ICF syndrome do seem to come from mutant DNMT3B induced miRNA dysregulation, only chromatin structure is the mechanism, not DNA methylation.
Follow all of the epigenetic interactions in ICF syndrome for yourself in Epigenetics, July 2010.