The Tug1 lncRNA locus is essential for male fertility
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RESEARCH
Open Access
The Tug1 lncRNA locus is essential for male fertility Jordan P. Lewandowski1†, Gabrijela Dumbović2†, Audrey R. Watson2,3†, Taeyoung Hwang2†, Emily Jacobs-Palmer4, Nydia Chang1, Christian Much2, Kyle M. Turner5, Christopher Kirby5, Nimrod D. Rubinstein5, Abigail F. Groff1,6, Steve C. Liapis1, Chiara Gerhardinger1, Assaf Bester7,8, Pier Paolo Pandolfi7,8, John G. Clohessy7,8, Hopi E. Hoekstra4,5,9*, Martin Sauvageau10,11* and John L. Rinn1,2,3* * Correspondence: hoekstra@oeb. harvard.edu; martin.sauvageau@ ircm.qc.ca; [email protected] † Jordan P. Lewandowski, Gabrijela Dumbović, Audrey R. Watson and Taeyoung Hwang contributed equally to this work. 4 Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, 4109 BioLabs, Cambridge, MA 02138, USA 10 Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada 1 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Full list of author information is available at the end of the article
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. Keywords: Tug1, lncRNA, Fertility, DNA repressor, Cis-regulatory elements, RNA-seq, Allele-specific, Genetics, Genomics, Mouse
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as lo
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