A mammalian-like piRNA pathway in Axolotl indicates the origins of piRNA-directed DNA methylation

November 2025, O’Carroll Lab, The EMBO Journal

Authors

Xiang, X., Gao, A., Handler, D., Falcon, F., Rodriguez-Terrones, D., Nowoshilow, S., Liu, W., Tanaka, E.M., and O’Carroll, D. 

Summary

By Rayane Kaade, Ohkura Lab

PIWI-interacting RNAs (piRNAs) are small non-coding RNAs that are bound to PIWI proteins, and guide gene-silencing processes. They play a key role in protecting germ cells from transposable elements. In mammals, piRNAs direct DNA methylation to repress transposons. However, the evolutionary origin of this mechanism remains unclear.

In this paper, the authors investigate the evolutionary origins of the piRNA pathway. Xinyu and her team, show that the axolotl possesses a mammalian-like piRNA pathway. By analysing axolotl oocytes and testes, they demonstrate that this pathway closely resembles the mammalian system, including its likely ability to guide DNA methylation. This is notable because many other previously studied vertebrates primarily use piRNAs for post-transcriptional silencing rather than DNA methylation. The study also shows that PIWI proteins and other piRNA pathway components are present in the axolotl genome and are specifically expressed in the gonads.

These findings suggest that the piRNA-directed DNA methylation pathway arose early in vertebrate evolution and has been conserved from amphibians to mammals.

schematic of piRNA pathway
The signature of a functional piRNA pathway is cyclical amplification of piRNAs from cleaved target transposon transcripts resulting in a 10-nucleotide overlap between the source and the target (A). This is clearly visible in (B), showing 5’ nucleotide overlap frequency in small RNA sequencing of testis and oocyte samples from Axolotl.

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