We find that disrupting the miR-200–ZEB1 double-negative feedback loop leads to anovulatory infertility and widespread gene expression changes in the mouse pituitary. This study demonstrates the dramatic phenotypic and molecular consequences of disrupting repression of a single miRNA target. (2/2)

Huge thanks to Brenda Schulman and @jakobfarnung.bsky.social for the exceptionally collaborative effort from start to finish. We also thank @wyppeter.bsky.social, Lianne Blodgett, and Daniel Lin for their invaluable contributions to this work! (5/5)

Our results establish AGO binding and polyubiquitylation as the key regulatory steps of TDMD, define a unique class of cullin–RING E3 ligases that depend on CUL3 and ELOB/C, and reveal generalizable RNA- and protein-mediated interactions that specify AGO degradation with exquisite selectivity. (4/5)

We demonstrate selective binding of ZSWIM8 to a human AGO–microRNA–trigger complex for CUL3-mediated polyubiquitylation of the AGO protein. Furthermore, cryo-EM analyses reveal how ZSWIM8 recognizes the distinct AGO and RNA conformations shaped by pairing of the microRNA to the trigger. (3/5)

The ZSWIM8 E3 ligase was known to cause degradation of AGO–microRNA complexes bound to trigger RNAs. However, whether and how ZSWIM8 directly recognizes these complexes among the preponderance of non-trigger-bound AGO–microRNA complexes in the cell has been a mystery. (2/5)

Check out related work by the Mendell lab (@mendell-lab.bsky.social) and the Xie lab: www.biorxiv.org/content/10.1..., www.biorxiv.org/content/10.1... (3/3)

We identify 5 sites in 3' UTRs of mRNAs that trigger target-directed microRNA degradation (TDMD) of miR-335-3p, miR-322, and miR-503, uncovering noncoding functions of these mRNAs. This study positions TDMD within imprinted gene networks on the battleground of parental conflict (2/3)

We've uncovered two mechanisms that coronaviruses use to solve the “tailomere problem” and identified an mRNA degradation pathway that operates independently of viral protein nsp1. Many thanks to Eugene Valkov's lab (@eugenevalkov.bsky.social) for their help with this study.

Since their discovery, we have known lysosomes possess RNase activity; however, their endogenous substrates were not known. Surprisingly we found preferential targeting of specific RNAs for lysosomal degradation by autophagy and identified sequence motifs that mediate their lysosomal targeting (2/2)

We developed a neural network machine-learning model that predicts poly(A) tail-length changes in frog, mouse, and human oocytes, revealing new regulatory motifs and showing that variants disrupting tail lengthening are under negative selection, thus linking tail-length control to human fertility.

We report that some miRNAs are capable of high affinity binding to 3′-only sites (stretches of extensive perfect pairing to the 3′ region, without any pairing to the miRNA seed) and that these sites are functional, imparting post-transcriptional repression to site-containing reporter mRNAs. (2/2)