Research Paper Volume 13, Issue 10 pp 13764—13787

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

Tie-Cheng Sun1,2, *, , Yi Zhang5, *, , Kun Yu6, *, , Yao Li6, , Hong Yu1, , Shan-Jie Zhou1, , Ya-Peng Wang4, &, , Shou-Long Deng3, , Li Tian1,2, ,

  • 1 Reproductive Medical Center, Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing 102206, China
  • 2 Reproductive Medicine Centre, Peking University Second Affiliated Hospital, Beijing 100044, China
  • 3 Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China
  • 4 Center of Reproductive Medicine, Peking University Third Hospital, Beijing 100191, China
  • 5 Department of Medicine, Panzhihua University, Sichuan 16700, China
  • 6 Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
* Equal contribution

Received: June 24, 2020       Accepted: November 8, 2020       Published: May 6, 2021
How to Cite

Copyright: © 2021 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


RNA-seq: RNA sequencing; ncRNA: non-coding RNA; lncRNAs: long non-coding RNAs; miRNAs: microRNAs; piRNA: PIWI-interacting RNA; 3’UTR: 3’untranslated region; GO: gene ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; DE: differentially expressed; NS: normozoospermic sample; OS: oligozoospermic sample; SRP9: signal-recognition particle 9; BMI: body mass index; DFI: DNA fragmentation index; FSH: follicle-stimulating hormone; LH: luteinizing hormone; T: testosterone; BP: biological process; CC: cell component; MF: molecular function.