DAZL Regulates Germ Cell Survival through a Network of PolyA-Proximal mRNA Interactions

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Abstract

The RNA binding protein DAZL is essential for gametogenesis, but its direct in vivo functions, RNA targets, and the molecular basis for germ cell loss in Dazl-null mice are unknown. Here, we mapped transcriptome-wide DAZL-RNA interactions in vivo, revealing DAZL binding to thousands of mRNAs via polyA-proximal 3′ UTR interactions. In parallel, fluorescence-activated cell sorting and RNA-seq identified mRNAs sensitive to DAZL deletion in male germ cells. Despite binding a broad set of mRNAs, integrative analyses indicate that DAZL post-transcriptionally controls only a subset of its mRNA targets, namely those corresponding to a network of genes that are critical for germ cell proliferation and survival. In addition, we provide evidence that polyA sequences have key roles in specifying DAZL-RNA interactions across the transcriptome. Our results reveal a mechanism for DAZL-RNA binding and illustrate that DAZL functions as a master regulator of a post-transcriptional mRNA program essential for germ cell survival. Combining transgenic mice, FACS, and multiple RNA-profiling methods, Zagore et al. show that DAZL binds thousands of mRNAs via GUU sites upstream of polyA tails. Loss of DAZL results in decreased mRNA levels for a network of genes that are essential for germ cell proliferation and differentiation.

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Zagore, L. L., Sweet, T. J., Hannigan, M. M., Weyn-Vanhentenryck, S. M., Jobava, R., Hatzoglou, M., … Licatalosi, D. D. (2018). DAZL Regulates Germ Cell Survival through a Network of PolyA-Proximal mRNA Interactions. Cell Reports, 25(5), 1225-1240.e6. https://doi.org/10.1016/j.celrep.2018.10.012

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