Macrolide antibiotics as modulators of translation

Macrolide antibiotics inhibit protein synthesis by targeting the bacterial ribosome. Because macrolides bind at the nascent peptide exit tunnel and partially block it, they have been thought to stop the synthesis of all proteins. However, recent evidence has demonstrated that macrolides interrupt translation depending on the sequence of the nascent protein. The context-specific action of macrolides impacts the regulation of the expression of resistance genes. Understanding the mechanism of action of macrolides not only may contribute to the rational design of better antibiotics but also reveals how small molecules affect the functions of the ribosome and modulate translation.

TBA

TBA

TBA

TBA

Non-coding small RNAs as versatile regulators of germline gene expression programs

The RNA-guided targeting of nucleic acids is an ancient and conserved mechanism of cellular immunity that has been evolutionary adapted and diversified to regulate eukaryotic gene expression. In animal germ cells, PIWI-interacting small RNAs (piRNAs) have been extensively characterized as a defense mechanism targeting transposable elements (TEs) to promote fertility and genome integrity. In a nutshell: loaded into PIWI effector proteins, piRNA sequences provide mRNA targeting specificity by antisense-complementarity, promoting gene silencing through a variety of mechanisms. Yet, piRNA sequences do not necessarily match TEs, pointing to extended possibilities in gene regulation.

Studying piRNA pathway functions in the context of the developing C. elegans germline we show that spermatogenic genes are susceptible to piRNA-mediated transcriptional silencing, and this function is required to ensure proper germline gene expression patterning and germ cell differentiation. In addition, our work revealed an intriguing aspect of small RNA biology: piRNA pathway components localize into diverse and distinct phase separated condensates present in the nuclear periphery. These condensates, also known as germ granules, are enriched in RNA-binding proteins and RNAs and are suspected to regulate post-transcriptional processes important for germ cell fate specification and function. Our results show that the organization of germ granules changes dynamically during development, and only a particular configuration enable nuclear piRNA silencing at a specific time and location in the germline tissue. This suggests that changes in germ granule composition directly influence nuclear processes through the modulation of small RNA related activities.

Overall the results of this work show that the function of piRNAs can be repurposed to regulate endogenous transcriptional programs during development and might contribute to expand the notion that piRNAs do not only function as a cellular immune system but also act as extremely versatile regulators of gene expression in animals.