The Tug1 lncRNA locus is essential for male fertility

Genome Biology

Taeyoung Hwang¹  Audrey R. Watson¹  Gabrijela Dumbović¹  Christian Much¹  John G. Clohessy²  Pier Paolo Pandolfi²  Assaf Bester²  Christopher Kirby³  Nimrod D. Rubinstein³  Kyle M. Turner³  Emily Jacobs-Palmer⁴  Hopi E. Hoekstra⁴  Abigail F. Groff⁵  Jordan P. Lewandowski⁵  Chiara Gerhardinger⁵  Nydia Chang⁵  Steve C. Liapis⁵  John L. Rinn⁵  Martin Sauvageau⁶ 

[1] BioFrontiers Institute, University of Colorado at Boulder;Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School;Department of Molecular and Cellular Biology, Harvard University;Department of Organismic and Evolutionary Biology, Harvard University;Department of Stem Cell and Regenerative Biology, Harvard University;Montreal Clinical Research Institute;

关键词: Tug1;    lncRNA;    Fertility;    DNA repressor;    Cis-regulatory elements;    RNA-seq;   

DOI  :  10.1186/s13059-020-02081-5

来源: DOAJ

【 摘 要 】

Abstract Background Several long noncoding RNAs (lncRNAs) have been shown to function as components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, studying lncRNA function has been a challenge due to their diverse biological roles and because lncRNA loci can contain multiple molecular modes that may exert function. Results We previously generated and characterized a cohort of 20 lncRNA loci knockout mice. Here, we extend this initial study and provide a more detailed analysis of the highly conserved lncRNA locus, taurine-upregulated gene 1 (Tug1). We report that Tug1-knockout male mice are sterile with underlying defects including a low number of sperm and abnormal sperm morphology. Because lncRNA loci can contain multiple modes of action, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region have any activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors two distinct noncoding regulatory activities, as a cis-DNA repressor that regulates neighboring genes and as a lncRNA that can regulate genes by a trans-based function. We also show that Tug1 contains an evolutionary conserved open reading frame that when overexpressed produces a stable protein which impacts mitochondrial membrane potential, suggesting a potential third coding function. Conclusions Our results reveal an essential role for the Tug1 locus in male fertility and uncover evidence for distinct molecular modes in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.

【 授权许可】

Unknown