LncRNAs induce oxidative stress and spermatogenesis by regulating endoplasmic reticulum genes and pathways

Abstract

Oligozoospermia or low sperm count is a leading cause of male infertility worldwide. Despite decades of work on non-coding RNAs (ncRNAs) as regulators of spermatogenesis, fertilization, and male fertility, the literature on the function of long non-coding RNAs (lncRNAs) in human oligozoospermia is scarce. We integrated lncRNA and mRNA sequencing data from 12 human normozoospermic and oligozoospermic samples and comprehensively analyzed the function of differentially expressed lncRNAs (DE lncRNAs) and mRNAs (DE mRNAs) in male infertility. The target genes of DE lncRNAs were identified using a Gaussian graphical model. Gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways were primarily enriched in protein transport and localization to the endoplasmic reticulum (ER). The lncRNA–mRNA co-expression network revealed cis- and trans-regulated target genes of lncRNAs. The transcriptome data implicated DE lncRNAs and DE mRNAs and their target genes in the accumulation of unfolded proteins in sperm ER, PERK-EIF2 pathway-induced ER stress, oxidative stress, and sperm cell apoptosis in individuals with oligozoospermia. These findings suggest that the identified lncRNAs and pathways could serve as effective therapeutic targets for male infertility.

lncRNA AGAP2-AS1 Facilitates Tumorigenesis and Ferroptosis Resistance through SLC7A11 by IGF2BP2 Pathway in Melanoma

“…lncRNAs were transcribed by RNA polymerase II, then modified by cap at the 5′end and splicing and polyadenosine acidification at the 3′end [ 28 ]. At first, it was thought to have no biological function, but the results of many experiments tell us that lncRNAs regulate gene expression at many levels in the form of RNA, such as transcription, posttranscriptional level, and epigenetics [ 29 , 30 ]. lncRNAs work mainly through the following four ways: first, induction, lncRNAs can bind to a specific miRNA, which can indirectly regulate the target gene; second, lncRNAs can act as a signal molecule on the pathway and regulate the upstream- and downstream-related genes of its target gene [ 31 , 32 ].…”

The Role of Long Noncoding RNAs on Male Infertility: A Systematic Review and In Silico Analysis

“…One more article was also excluded, as it was a perspective and did not present original data. Finally, a total of 20 articles remained to be included in the present systematic review [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

“…More specifically, Sun et al (2021) [ 37 ] examined the expression profile of lncRNAs in oligozoospermia, and found 2364 differentially expressed lncRNAs between oligozoospermic and healthy males. A total of 464 lncRNAs were downregulated, while 1900 lncRNAs were upregulated ( Table S3 ).…”

“…COX10 antisense RNA 1 ( COX10-AS1 ) is another lncRNA that was found to be upregulated in patients with teratozoospermia [ 45 ] and asthenozoospermia [ 41 ], and is also deregulated in oligozoospermia [ 37 ]. Until now, little was known about the role of COX10-AS1 in human diseases; however, many studies associate it with human cancers as well.…”

Long Noncoding RNAs: Recent Insights into Their Role in Male Infertility and Their Potential as Biomarkers and Therapeutic Targets

“…Several lncRNAs-miRNAs were shown to be involved in the regulation of spermatogenesis, including lncRNA LOC105607399 and LOC105610178. Moreover, another recent study revealed that lncRNAs and mRNAs were abnormally expressed in patients with oligozoospermia and the proportion of downregulated lncRNAs and mRNAs was less than that of upregulated ones [109].…”