Loss of PIWIL4-piRNA interaction reveals uncertain somatic epigenomic evolution

Analyzing genomic and epigenomic changes that are either randomly or causally induced enhances precision medicine. Knockout (KO) of the Piwi-interacting RNAs (piRNA)-interacting genes PIWIL4 or L1TD1 in cancer and normal cells may unleash the oncogenic evolution to produce genomic alterations and subsequent alternations. Our findings show that whereas the binding motifs of important epigenetic markers (CTCF, acetylated histone H3 at lysine 27, and trimethylated histone H3 at lysine 9) were maintained in KOs, their global binding sites were markedly changed. Changes in transposable element abundance, chromatin conformation, transcript variations, and gene expression profiles were all found at the same time. Additionally, we discovered new oncogenic insertions and deletions (indels) in the coding sequences of the KOs, indicating separate gene evolution. Our findings also show an unanticipated epigenomic evolution through altered chromatin locations and evolutionary rates. Significantly, we discovered similar patterns of altered transcript variants, increased indels, and transposable element shifts in a number of models, including models of myeloproliferative neoplasm (MPN) expressed by JAK2V617, aged mesenchymal stem cells, SARS-CoV-2 replicon-expressed cells, and a fetal alcohol syndrome rat model. Genetic reversion was unable to restore these modified transcript variants or transposable element abundances, according to a convincing finding from an MPN model. These results offer strong support for piRNAs' role in somatic genome protection and a potential uncertainty law in epigenomic evolution. (Supported by NSTC 114-2320-B-194 -001, Taiwan)