Drosophila Modulo is essential for transposon silencing and developmental robustness.

Journal of Biological Chemistry. Mar2025, Vol. 301 Issue 3, p1-12. 12p.

Transposable element (TE) silencing in the germline is crucial for preserving genome integrity; its absence results in sterility and diminished developmental robustness. The Piwiinteracting RNA (piRNA) pathway is the primary small noncoding RNA mechanism by which TEs are silenced in the germline. Three piRNA binding proteins promote the piRNA pathway function in the germline-P-element-induced wimpy testis (Piwi), Aubergine (Aub), and Argonaute 3 (Ago3). Piwi mediates transcriptional silencing of TEs by promoting the deposition of the heterochromatin mark Histone 3 lysine nine trimethylation (H3K9me3) at TE genomic sites. Aub and Ago3 facilitate post-transcriptional silencing of TEs. Proteins and mechanisms that promote piRNA function in TE silencing are still being discovered. This study demonstrates that the Drosophila Modulo protein, a homolog of mammalian Nucleolin and an epigenetic regulator, is crucial for the enrichment of H3K9me3 at TEs. We show that Modulo interacts with Piwi and operates downstream of the Piwi-piRNA complex's entry into the nucleus. Lack of Modulo function impairs Piwiinteracting protein Panoramix's ability to target transposon RNAs. Furthermore, the reduced function of Modulo in the mother undermines developmental robustness and exacerbates neomorphic Kr[If-1]-induced ectopic eye outgrowths in the offspring. Maternal Modulo enhances developmental robustness by inhibiting TE activation and transcriptome variability associated with intrinsic genetic variation. Thus, Modulo is an essential component of the mechanism that operates in the maternal germline to facilitate TE silencing and ensure developmental robustness in the ensuing generation. [ABSTRACT FROM AUTHOR]

*Carrier proteins, *Genetic variation, *Non-coding RNA, *Nucleolin, *Heterochromatin

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