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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 1  |  Page : 18-22

Role of Related Regulatory Long Noncoding RNAs on Mammalian Spermatogenesis


1 Department of Clinical Laboratory, State Key Laboratory of Reproductive Medicine, Nanjing Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China
2 Department of Endocrinology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
3 Department of Andrology, State Key Laboratory of Reproductive Medicine, Nanjing Obstetrics and Gynecology Hospital, Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China
4 Department of Reproduction, State Key Laboratory of Reproductive Medicine, Nanjing Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China

Date of Web Publication17-Jul-2017

Correspondence Address:
Ling-Juan Gao
Department of Clinical Laboratory, Nanjing Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029
China
Xiu-Feng Ling
Department of Reproduction, State Key Laboratory of Reproductive Medicine, Nanjing Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.210690

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  Abstract 


Long noncoding RNAs (lncRNAs) are transcribed by RNA molecules, which are longer than 200 nucleotides that lack an open reading frame of significant length and possess no obvious protein-coding capacity. Studies have shown that lncRNAs participate in many physiological processes such as gene imprinting and X chromosome inactivation. They regulate gene expression mainly through DNA methylation, histone modification, and chromatin remodeling. LncRNAs can also affect the development of diseases, and they can be useful to diagnose and treat diseases. With the development of new sequencing and microarray techniques, hundreds of lncRNAs involved in spermatogenesis have been identified, but their functions in the testis are undefined. Herein, we will discuss the biology and regulation of lncRNAs, as well as the bioinformatics tools and searchable databases used to study them in the testis. We hope that this information will provide new insights in treating male reproductive diseases.

Keywords: Epigenetics; Long Noncoding RNA; Long Noncoding RNA Database; Spermatogenesis


How to cite this article:
Liu KS, Mao XD, Pan F, Gao LJ, Ling XF. Role of Related Regulatory Long Noncoding RNAs on Mammalian Spermatogenesis. Reprod Dev Med 2017;1:18-22

How to cite this URL:
Liu KS, Mao XD, Pan F, Gao LJ, Ling XF. Role of Related Regulatory Long Noncoding RNAs on Mammalian Spermatogenesis. Reprod Dev Med [serial online] 2017 [cited 2020 Aug 13];1:18-22. Available from: http://www.repdevmed.org/text.asp?2017/1/1/18/210690

Kang.Sheng Liu and Xiao.Dong Mao contributed equally to this work.





  Introduction Top


Higher organisms transcribe large amounts of RNAs, however, only a fraction of these transcripts encode proteins or polypeptides, which occupy only 2% of the entire genome. The rest transcripts are noncoding RNAs (ncRNAs). Based on the length of the RNA, ncRNAs can be further classified as small noncoding RNAs (sncRNAs, <200 nt) or long noncoding RNAs (lncRNA, >200 nt). NcRNAs, which were long, thought to be transcriptional noise because they lack biological functions.[1] On the other hand, of all the transcripts in the human genome, only 1.2% are mRNAs, and the others are ncRNAs, suggesting that ncRNAs may have important roles in organisms.[2] SncRNAs regulate the expression of target genes at both transcriptional and posttranscriptional levels.[3],[4] LncRNAs are polyadenylated and catalyzed by RNA polymerase II and found in the nucleus and cytoplasm where they possess various biological functions.[5],[6]

According to the World Health Organization survey, 15% of childbearing-age couples are infertile, and in developing countries, it can be 30%. With the aggravation of environmental problems, food safety issues, and electromagnetic radiation, the incidence of infertility is on the rise.[7],[8] Male factors are responsible for half of these cases.[9] Although the assisted reproductive technologies, such as in vitro fertilization and intracytoplasmic sperm injection, have helped some infertile males. However, a larger proportion of male victims, their causes for infertility are still unknown (e.g., nonobstructive azoospermia or nonocclusive azoospermia). This becomes a bottleneck for clinical treatment.[10]

A man produces more than 100 million sperm a day through spermatogenesis. After a complex and precisely regulated process, fertilizable gametes are produced. Although hundreds of genes are turned on and off during spermatogenesis,[11] transcription ceases in round spermatids (RS) and genes are regulated posttranscriptionally by ncRNAs. For example, lncRNAs participate in the proliferation, differentiation, and self-renewal of stem cells, including embryonic stem cells, induced pluripotent stem cells, and spermatogonial stem cells (SSCs). They also play roles in the regulation of the cell cycle, apoptosis, and the inhibition of reproductive system tumors.[12],[13],[14],[15],[16] LncRNAs may be useful biomarkers to detect spermatogenic abnormalities. Herein, we will review the biology and regulation of lncRNAs, as well as highlight the research methods used to study them. Special emphasis will be placed on the functions of lncRNAs in spermatogenesis.


  Classification of LNCRNAs Top


With the introduction of high-throughput sequencing, thousands of lncRNAs have been identified, characterized, and categorized. However, there is no consensus on how they should be categorized.

According to different origins, lncRNAs can be classified into five categories as follows:[17],[18] (i) tandem duplicates in adjacent repeat units; (ii) juxtaposed and restructured lncRNAs in untranscribed and separated gene sequence during chromosome recombination; (iii) duplicates of nonencoding genes in reverse transcription; (iv) lncRNAs produced due to frame fracture of protein-coding genes; and (v) lncRNAs produced by transposable element insertion.

According to its positional relationship with neighboring protein-coding genes, lncRNAs can be classified as follows: (i) antisense lncRNA; (ii) intronic lncRNA; (iii) divergent lncRNA; (iv) intergenic lncRNA; and (v) enhancer lncRNA.


  Lncrna Databases Top


With recent advances in the field of ncRNAs, information on their biological characteristics (e.g., gene organization characteristics, sequence conservation, expression profiles, molecular interactions, epigenetic modifications, and functional annotation) increases with time. At present, few investigators have established lncRNA information databases, which provide basic information on lncRNAs (e.g., primary sequence and genome seat). One of these databases, the deep Base database, integrates the analytical process of lncRNA identification based on the RNA-seq data set, thereby providing lncRNA expression profile data from 478 data sets of 14 species, predicting functions, and analyzing the evolutionary conservation of these lncRNAs (http://biocenter.sysu.edu. Cn/deep Base/index. php).[19] The DIANA-LncBase database is a collection of experimental evidence and miRNA-lncRNA target relationships predicted by the DIANA-micro T algorithm.[20] The ChIP-Base database provides information on how transcription factors regulate lncRNAs and miRNAs (http://deepbase.sysu.edu.cn/chipbase/index.php).[21] The lncRNA database is a relatively professional database to date, including comprehensive annotation of lncRNAs in eukaryotic organisms (http://www.lncrnadb.org/).[22] LncRNADisease is a Chinese database of lncRNAs and human diseases, containing data of multiple lncRNAs and their relevance to human diseases.[23] LNCipedia provides the primary sequence and secondary structure of human lncRNAs and evaluates the protein transcriptional potential of lncRNA with bioinformatic tools and ribosome sequencing data.[24] LncRNASNP also includes information on single-nucleotide polymorphisms in human and mouse lncRNAs, data from the genome-wide association study (GWAS), and their impact on lncRNA structure and lncRNA-miRNA combination.[25] LncR Nome is developed by the Indian Institution of CSIR Genome and Integrative Biology. It provides stable annotations, cross-references, and biologically relevant information and resources that support biological significance of lncRNAs and integrate it into the comprehensive knowledge base.[26]

NONCODE organizes the full-scale information of lncRNAs in 16 species, including the location, sequence, expression profile, evolutionary conservation, functional annotation, and relevant diseases.[27] A microRNA target database, supported by high-throughput experimental data (CLIP-Seq, aka, PAR-CLIP, and iCLIP) and mRNA degradome sequencing data, describes the regulatory relationships between micro RNA (miRNA) and mRNA, miRNA and lncRNA, miRNA and circRNA, miRNA and ceRNA, and RNA and protein. This database integrates and constructs intersections and regulatory relationships among multiple popular target prediction platforms and establishes the ceRNA regulatory network to predict lncRNA functions.[28] LncRNAtor collects data from TC-GA, GEO, ENCODE, and mod ENCODE, and compiles lncRNA expression profiles for cancer samples, as well as provides protein-coding gene co-expression analysis and gene ontology (GO) enrichment analysis of co-expressed genes.[29] It provides information on the differential expression of lncRNAs, identifies tissue or cellular expression with specific microarray, and confirms the results by qPCR. The interference and overexpression of RNA can be used to study specific lncRNA functions.


  Function of Lncrnas in Spermatogenesis Top


Function of long noncoding RNAs

LncRNAs are by-products of Pol II transcription and long thought to be transcriptional noise with no biological function.[30],[31] However, more and more studies indicated that lncRNAs were not the “dark matter” of the genome, and lncRNAs were found to be involved in DNA methylation or demethylation, RNA interference, histone modification, and chromatin remodeling in spermatogenesis and fertilization.[32],[33],[34],[35],[36],[37],[38] Some lncRNAs are precursors of some functional sn-cRNAs (e.g., miRNAs, siRNAs, and piwiRNAs) that indirectly regulate target genes.[38]

LncRNAs possess spatial- and temporal-specific expressions,[39] and they execute their biological functions as follows:[6] (i) recruit chromatin to modify related enzymes, and direct the protein complex to the regulatory sites in cis- or trans-orientation (as guide molecules), (ii) bind directly with transcription factors and proteins to block their actions on target genes, regulating target gene transcription indirectly (as bait molecules), (iii) regulate target genes by identifying the key transcription factors in various signaling pathways (as signaling molecules), and (iv) recruit proteins to form ribonucleoprotein complexes, thereby regulating target genes at the epigenetic level through histone modification (as scaffold molecules).

Unlike mRNAs, lncRNAs are not conserved in primary sequence, except that promoter region and splicing site is conserved.[40] This feature endows lncRNAs with highly conserved secondary and tertiary structures, which are crucial to their biological functions.

Genetic and epigenetic mechanisms are involved in gene expression during, as well as after, transcription. DNA methylation, a key epigenetic modification, plays a critical role in spermatogenesis.[41] A recent study suggested that the expression of lncRNAs is dynamically regulated on the development of male germ cells. Analyzed by ArrayStar on mouse lncRNA, the expression of lncRNAs and mRNAs at six time points (E12.5, E15.5, P7, P14, P21, and adult) was evaluated. They also found that the high level of lncRNAs was closely correlated with the expression level of adjacent mRNAs (<30 kb).[42]

In 2013, results from a study of Sun et al.[43] represented the first systematic investigation of lncRNA expression in the mammalian testis. They employed microarray technology to examine lncRNA expression profiles of neonatal (6-day-old) and adult (8-week-old) mouse testes. They found that 8,265 lncRNAs were expressed above background levels during postnatal testis development, of which 3,025 were differentially expressed. Candidate lncRNAs were identified for further characterization by an integrated examination of genomic context, GO enrichment of their associated protein-coding genes, promoter analysis for epigenetic modification, and evolutionary conservation of elements. Many lncRNAs overlapped or were adjacent to key transcription factors and other genes involved in spermatogenesis. Most differentially expressed lncRNAs exhibited epigenetic modification marks similar to protein-coding genes and tend to be expressed in a tissue-specific manner. In addition, the majority of differentially expressed lncRNAs harbored evolutionary conserved elements.

In 2014, results from a study of Liang et al.[44] suggested that the sequential expression of lncRNA as mRNA gene expression exhibits coordinated changes in male spermatogenesis. They profiled the expression of lncRNAs and mRNAs in each type of germ cells (SSCs, type A spermatogonia [A], pachytene spermatocytes [PS], and RS) by microarray analysis. They analyzed the total expression of lncRNA/mRNA in these four germ cells and found that the maximum number of lncRNAs expression is in A (22,127), and the minimum is in PS (14,456). In addition, the maximum number of mRNAs is in A (19,923), and the minimum is in PS (13,941). Furthermore, the trend in the number of specific lncRNAs was similar to the number of specific mRNAs in each type of germ cells (e.g., maximum in A and minimum in PS). The trend in the number of lncRNAs was similar to the number of mRNAs in two continued types of germ cells (e.g., maximum in SSC to A and minimum in PS to RS).

LncRNA Neat1, Malat1, Mrh1, HongrES2, narcolepsy candidate-region 1 gene expression in spermatogenesis

SSCs differentiate into sperm through spermatogenesis, which involves various genes such as Bcl6b, Etv5, Kit L, and EPCAM. Neat1, a 3.2 kb lncRNA, participates in the formation of paraspeckles structure. Neat1, along with other protein-RNA complex, also participates in the modification of genes' transcription. In 2012, Nakagawa et al.[45] found that Malat1 (a type of lncRNA) was embedded in the subnuclei of cells, and with pre-mRNA regulates many biological processes, such as the growth of synapses and change of cellular cycles. In 2014, An et al.[37] found that Neat1 was expressed in rat testicular tissues and GC-l cell lines. After the injection of lentiviruses, testicular indexes in the experimental group rose, but not significantly. At the same time, the proportion of seminiferous tubules harboring sperms dropped to 86%, indicating that Neat1 regulated rat spermatogenesis.

With a length of 2.4 kb, Mrhl is a type of single-axon lncRNA encoded by the nuclear genome and expressed in testes.[46] In 2008, Ganesan and Rao [47] found that Mrhl can regulate spermatogenesis through two molecular mechanisms. First, Mrhl is divided by Drosha into a midbody of 80 nt. These RNAs are located in the nuclei of GC1 spermatogonial lines, probably interacting with chromatin. Second, Wnt is critical to mammalian spermatogenesis.[48] Cooperating with p68, Mrhl shows its negative regulation in Wnt signal. Knockdown Mrhl expression in GC-1 SPg cell line can disrupt the expression of genes that are responsible for cell signal transduction and development. Most of these genes are members of the Wnt signaling pathway which known to promote cell differentiation and inhibit cell growth. Therefore, Mrhl is crucial for spermatogonial division and differentiation.[49] Further studies are needed in gene knockout mice to define the function and regulation of Mrhl in spermatogenesis.

Male infertility is often caused by maturation arrest (MA). HongrES2 is a 1,588-nt lncRNA co-transcribed by rats' chromosome 5 and 9 and expressed in testis; its expression increases at the end of the first round of spermatogenesis. Space-time specificity of this expression is manifested in the spermatogenesis. Mil-HongrES2, the spliced HongrES2, can downregulate the expression of CES7, the products of which show an important role in capacitation.[50] Interestingly, nuclei weakly express mil-HongrES2, but strongly express HongrES2, indicating that an unknown splicing mechanism exists. Therefore, HongrES2 can regulate the maturating process of sperms.[49] Besides, the overexpression of mil-HongrES2 can weaken spermatic capacitation, indicating the contribution of lowly expressed endogenic HongrES2 to spermatic development.[51]

Narcolepsy candidate-region 1 gene (NLC1-C) is cytoplasmic lncRNA expressed in spermatogonia and early spermatocytes. NLC1-C overexpression promotes cell growth, whereas its loss inhibits cell growth and accelerates apoptosis. Microarray analysis indicated NLC1-C was lower expressed in MA patients than normal person. In another study, NLC1-C was reported to bind to the RNA-binding domain of nucleolin, which inhibited the transcription of miR-320a and miR-383 and induced the proliferation of spermatogonia and early spermatocytes in MA patients.[52]

LncRNAs fine-tune the global genes expression

With the development of high-throughput sequencing, it was found that “dark matters” in eukaryotic genomes were highly and specifically expressed lncRNA in testicular tissues. This expression is an important phenomenon in spermatogenesis. Using the CRISPR system, Wen et al.[53] reported that 1/3 loss of lncRNA could disorder spermatogenesis in Drosophila. Knocked-out lncRNAs of some Drosophila could be repaired with translocation, suggesting the transfunction of lncRNAs. According to gene expression profile, most functional lncRNAs participate in the global genes expression during spermatogenesis. According to relative evolution analysis, lncRNAs evolve faster than encoding genes. The more functions lncRNAs have, the more sequence conservation they show. Different from the switch of encoding genes, lncRNAs regulate the global expression through fine-tune, indicating their promoting role in spermatogenesis.[53]


  Results and Future Perspectives Top


More and more lncRNAs were reported that they participated in spermatogenesis, including cell growth and cell differentiation. Unlike miRNAs, lncRNAs are less conservative. The function of lncRNA should be further studied. Nonconservative lncRNAs have overlapped functional domains. LncRNAs have various functions with various factors, such as decoy molecules, guide molecules, and scaffold molecules. All these molecules are engaged in the expression. As a form of epigenetic regulation, lncRNAs may function in reproductive processes (like spermatogenesis) through histone modification and chromatin reconstruction. Different expressions of lncRNA, Neat1, Mrhl, and HongrES2 build up a regulating network in spermatogenesis, providing us a new perspective to look into the essence of male reproduction. Besides, lncRNAs regulate the global expression through fine-tune, indicating their promoting role in spermatogenesis.

Further studies are needed to understand the roles of lncRNAs in spermatogenesis. With the rapid development of new technologies and searchable databases, such as bioinformatic tools and ontology databases, lncRNAs may serve as biomarks and/or targets to diagnose and/or treat male infertility in future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
Lncrna Databases
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