Starting from Scratch: DNA Methylation Marks Erased Through 5-hmC in Primordial Germ Cells
A growing body of evidence indicates that ancestral environmental factors can influence the physiology and behavior of the offspring, a process known as epigenetic inheritance. However, in each generation the epigenetically inherited modifications are thought to be erased in cells called primordial germ cells (PGCs), the precursors to sperm and eggs, leaving scientists to question how epigenetic inheritance occurs. In a recent paper published in Science, researchers from the University of Cambridge investigated how mouse PGCs reset their epigenetic modifications and remove DNA methylation on a genome-wide scale during development in an effort to learn more about trans-generational epigenetic inheritance.
The authors observed that decreases in the levels of 5-methylcytosine (5-mC) are associated with an increase in the levels of 5-hydroxymethylcytosine (5-hmC) in PGCs between embryonic day (E) E9.5 and E10.5, leading them to suggest that 5-mC modifications may be converted to 5-hmC in the process of erasure of DNA methylation and epigenomic reprogramming in these cells. In support of this idea, they showed that both TET1 and TET2, enzymes known to be responsible for cytosine demethylation, are present in the nuclei of PGCs and their levels are higher in these cells than in neighboring somatic cells.
While increased levels of the TET enzymes might explain the majority of the DNA demethylation during PGC development, there is definitely more to the story due to the fact that the authors also identified multiple areas of the mouse genome where DNA methylation was not erased. This finding is especially interesting because it potentially provides a mechanistic explanation for trans-generational epigenetic inheritance. The majority of the regions that escape the erasure of DNA methylation were in repetitive DNA elements, but several single-copy genes that maintained their DNA methylation patterns were also discovered. The genomic regions where DNA methylation levels persisted during PGC development did not share any primary sequence motifs, suggesting that histone modification or chromatin dynamics might be important contributing factors to specify locations that will contain the heritable epigenetic signatures.
The findings of Hackett et al. may provide mechanistic avenues for investigations into trans-generational epigenetic inheritance in the near future. Further studies into this direction could provide more detailed information on how to erase aberrant epigenetic marks that may contribute to some diseases in adults, thus preventing these modifications from being spread to future generations.
Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, & Surani MA (2013). Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science (New York, N.Y.), 339 (6118), 448-52 PMID: 23223451