If you’re underperforming at work, you might end up with a rejected paper, failed experiments, or an angry boss. However, this isn’t so bad when compared to how mutated DNMT3A underperforms in its role as a DNA methyltransferase, since that can result in a pathogenic overgrowth known as Tatton-Brown-Rahman syndrome (TBRS). Despite DNMT3A’s known role in TBRS (germline mutations) and in blood cancers (somatic mutations), very little is known about what effects mutant DNMT3A has on the methylome. Thankfully, a team of high-performance researchers lead by Jonathan Mill, Andrew Crosby, and Emma Baple at the University of Exeter Medical School (Exeter, UK) have newly published research to figure it out.
The talented team initiated their study by examining a large Amish family, including four TBRS patients with the DNMT3A Arg771Gln mutation. Using the Illumina 450k array, they looked for site-specific differences in DNA CpG methylation by comparing the TBRS family members to unaffected siblings. They then expanded their analysis to include more TBRS patients and other DNA methyltransferase disorders.
Here’s what they found:
- Individuals with TBRS display extensive hypomethylation of genes related to growth, development, and differentiation
- This was observed for all tested DNMT3A mutational variants
- TBRS individuals have accelerated epigenetic aging
- Within the Amish family of DNMT3A Arg771Gln carriers, epigenetic age was ~40% greater than chronological age
- The greatest observed increase in epigenetic age was ~800% of the chronological age, which occurred in a patient with the germline DNMT3A mutation Arg882Cys – a common somatic mutation associated with acute myeloid leukemia (AML)
- Two other histone methyltransferase disorders, Sotos syndrome (overgrowth) and Kabuki syndrome (growth impairment), have increased or decreased epigenetic aging, respectively
Overall, the authors hypothesize that decreased DNMT3A function and the resulting hypomethylation found in TBRS patients could potentially promote increased proliferation of progenitor cells and decreased differentiation, resulting in the overgrowth syndrome phenotype.