Dnmt2 represents the lesser-known child of the DNA-methyltransferase family, but not because of any lack of pizazz or stage presence, but perhaps due to the lack of detectable DNA-cytosine methylation activity when compared to its more well-known brethren (Dnmt1 and Dnmt3). Instead of modifying DNA, Dnmt2 plays a big role in transfer RNA (tRNA) methylation to promote tRNA folding and structural stability and the modulation of chemical and biological properties. Now, new findings describe a role for Dnmt2 in shaping sperm RNA profiles.
Small non-coding RNAs (sncRNAs) in sperm (including tRNAs) represent crucial mediators of intergenerational effects, such as those related to paternal exercise and diet. However, the mechanisms how these mobile, trans-acting sperm sncRNAs encode this paternal information remained unclear until the publication of a new study from the laboratory of Qi Chen (University of Nevada, Reno, USA).
To gain insight into the intergenerational transmission of paternally acquired metabolic disorders the talented team employed Dnmt2-/- and Dnmt2+/+ male mice fed a high-fat diet (HFD = 60% fat, which led to obesity, glucose intolerance, and insulin resistance) or a normal diet (10% fat, not associated with metabolic disease) from 6 weeks to 6 months of age.
Here is all the big news about Dnmt2 and sperm small non-coding RNAs:
- Mice lacking Dnmt2 do not exhibit sperm sncRNA-mediated transmission of HFD-induced metabolic disorders to offspring
- Analysis of 13 different RNA modifications highlighted a lack of 5-methylcytosine (m5C) and 2-methylguanine (m2G) deposition in HFD-induced sperm sncRNAs in the absence of Dnmt2
- Interestingly, the lack of Dnmt2 activity also modulates the expression profile of sperm tRNA-derived small RNAs and rRNA-derived small RNAs
- The authors posit that the totality of sncRNAs and their modifications compose a sperm RNA “coding signature” required for paternal epigenetic memory
- The authors discovered that Dnmt2-mediated m5C deposition affects the secondary structure and biological properties of sncRNAs
- Therefore, sperm RNA modifications may represent an additional layer of paternal hereditary information
The authors of this fascinating new study suggest that a combination of sperm sncRNA types and modifications may interact with other RNA species to generate multiple synergistic effects during early embryo development. Moving forward, the team aims to discover just how Dnmt2 responds to the parental environment and encodes the sperm sncRNA signature.
For more on the big impact on Dnmt2 on sperm small RNAs, head over to Nature Cell Biology, 2018.