Testis-specific lncRNA Teshl regulates acrosome biogenesis to maintain sperm structure and function

The testis exhibits the highest tissue-specific gene expression of all organs, including both coding and non-coding genes. Our previous study reported that Teshl, a testis-specific long noncoding RNA, associates with heat shock factor 2 (HSF2), a transcription factor, to regulate Y chromosome gene expression and sperm fertility. We conducted an in-depth analysis of the function and molecular mechanisms of Teshl using Teshl-knockout (KO) mice. Remarkably, the absence of Teshl caused abnormal acrosome biogenesis during spermiogenesis, resulting in malformed and disorganized acrosomes and abnormal sperm head morphology. Teshl-KO sperm also exhibited altered acrosome reaction and reduced motility. A thorough examination of all available relevant datasets identified three Teshl-related proteins associated with acrosome structure and function: actin related protein T1 (ACTRT1), acrosin binding protein (ACRBP) and dickkopf-like acrosomal protein 1 (DKKL1). Our findings suggest that these proteins are directly or indirectly regulated by Teshl-HSF2 through transcriptional or protein-interaction mechanisms. The present findings significantly expand our understanding of the important roles of Teshl, a pioneering testis-specific lncRNA, by elucidating its acrosomal function and mechanism in male reproduction.