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lncRNAs: Role in Regulation of Gene Expression

Written By

Pranjal Kumar and Nikita Bhandari

Submitted: 22 February 2022 Reviewed: 12 April 2022 Published: 09 June 2022

DOI: 10.5772/intechopen.104900

Gene Expression IntechOpen
Gene Expression Edited by Fumiaki Uchiumi

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Gene Expression

Edited by Fumiaki Uchiumi

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Abstract

The long non-coding RNAs (lncRNAs) are a subclass of ncRNA which is more than 200 nucleotides long and processed similar to mRNA by RNA polymerase II with very few differences between them. In the last two decades, it has become a hot topic of research as it has been found differentially expressed in disease versus normal conditions including cancers. They regulate many biological functions including regulation of gene expression and epigenetic control. lncRNAs can control gene expression at the transcriptional level, and post-transcriptional level. Also, they can play a structural role to function as scaffolds for protein complexes. They interact with DNA, RNA, and proteins. They have been shown to possess competitive binding sites for miRNAs, which makes them a master regulator of gene expression by masking miRNAs and altering many biological functions. They are found to be associated with many cellular functions including cell proliferation, migration, and invasion. The lncRNAs can be utilized as biomarkers and can be targeted for personalized therapy.

Keywords

  • ncRNA
  • lncRNA
  • miRNA sponge
  • gene expression
  • biomarker
  • targeted therapy
  • epigenetic regulation
  • etc.

1. Introduction

Ribonucleic acid (RNA) is a biological macromolecule, which serves as genetic material as well as carries the information from deoxyribonucleic acid (DNA). RNAs are of multiple types and sub-categorized as per the functions they carry out, such as messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), etc. Among these, mRNA is called coding RNA as it gets translated into protein while others are considered non-coding RNAs (ncRNAs) with no coding potential. The ncRNAs have been studied since the 1950s, which were mostly limited to tRNA and rRNA. Later, microRNAs (miRNAs) were discovered and to date, it is the most studied ncRNAs. ncRNAs were further subdivided as per their sizes. The term lncRNA stands for long non-coding RNA. It has been sub-categorized as lncRNA having more than 200 nucleotides [1, 2].

The human genome consists of more than 100,000 lncRNA genes [3, 4]. They are mainly transcribed by RNA polymerase II which leads to the 5′-capping i.e. (addition of 7-methyl guanosine at the 5′-end), and polyadenylation at the 3′-end [5]. The processing of lncRNAs transcription is similar to that of mRNAs. Earlier it was thought to be junk, but recent advancements in the understanding of ncRNAs have found it as regulatory biomolecules. Although the total number of lncRNAs is always debatable with the number of functionally characterized lncRNAs. With the recent findings, it is clear that they are part of many biological processes and their regulation.

There are an increasing number of lncRNAs that are functionally characterized, but still, there is a need to have more pieces of evidence to support the recent findings. These lncRNAs are associated with many cellular functions including gene expression and regulation. lncRNAs have been shown to control many gene expressions, some of them control only neighboring gene expressions while some function at a distant position. They have structural and functional roles in the regulation of gene expression. Recent studies over the last decade show that they are part of the regulatory roles in embryonic development [6] as well as in human diseases including cancers [7, 8], heart diseases [9], etc. The lncRNAs functions have been found to be associated at the transcriptional level, translational level, and chromatin levels [10]. In this chapter, we are going to review lncRNA biology, from their biogenesis to functions mainly in gene expression and regulation.

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2. Genomic organization of lncRNAs

There are great numbers of noncoding regions (about 98–99% of the genome sequences in human) distributed between the coding region [11, 12]. The lncRNAs’ sequences are present throughout in the genome and can be studied as different types depending upon their location in the genome. The lncRNAs can be broadly categorized in five types based on their genomic location [6]. They are stand-alone (also called as long intergenic non-coding RNA), natural antisense lncRNAs (tend to be highly enriched near promoter or terminator regions), pseudogenes (extra copy of existing genes, which are no more capable of coding), long intronic lncRNAs (synthesized from the intronic region of already annotated genes) and divergent lncRNAs (close to the transcription start site, promoter or enhancer regions). These all types of transcripts are presented in Figure 1. They are classified as different types based on their genomic positions but it is not on the basis of their function which simply help in the organizing the diverse species of lncRNAs [6].

Figure 1.

Genomic organization of IncRNAs. IncRNAs are named as per their relative location corresponding to already annotated protein coding genes. Arrow denotes the direction of IncRNA gene sequence at their Transcription Start Site. Protein Coding Genes (exons) are shown in purple boxes, various types of IncRNAs are shown in different colors. In case of pseudogenic IncRNAs, it is premature termination of transcription (yellow color TGA).

The lncRNAs are synthesized from distinct genomic location, therefore, they have been named accordingly. The lncRNAs which come from intergenic regions are called as intergenic lncRNAs, also known as stand-alone lncRNAs. Similarly, the lncRNAs which are synthesized from intronic regions of a protein coding genes are called as intronic lncRNAs. All other types are also named as per their genomic location [6].

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3. Biogenesis and localization of lncRNAs

The lncRNAs are synthesized similarly to mRNA i.e. they are transcribed by RNA polymerase II, capped at 5′-end (m7G), poly-A tail at the 3′-end (polyadenylation), and spliced to remove introns. Figure 2a illustrates the comparison between the biogenesis of mRNAs and lncRNAs. Figure 2b (adapted from Chun-Jie Guo et al. 2020) [13] tells that a greater number of lncRNAs are found to be localized in the nucleus. The basic difference between the lncRNAs and mRNAs includes the sequence conservation and the number of exons. The lncRNAs are comparatively less conserved than mRNAs and they are composed of fewer exons [13, 14, 15].

Figure 2.

Biogenesis and Localization of IncRNAs. (a) Diagrammatic representation of IncRNA and mRNA transcription and the localization of IncRNAs in different cellular compartments for their function. (b) Some well studied IncRNAs at their respective cellular compartments (Chun-Jie Guo et al. 2020).

The expression of lncRNAs is controlled by histone modification at their promoter regions [16, 17]. Also, the phosphorylation status of RNA polymerase II defines the expression of lncRNAs. They are also transcribed by dysregulated RNA polymerase II, which leads to the accumulation of some faulty lncRNAs on chromatin which are soon degraded by ribonuclease complex known as RNA exosomes [18]. lncRNAs are found to be localized in the nucleus as well as cytoplasm. One of the reasons for their nuclear retention is somewhat associated with weak splicing signals i.e. the length of the segment between the branch point and 3′ splice site is comparatively longer than the length in mRNA [17, 19, 20]. Other factors, including splicing inhibitors [13] and alternative poly-A signals, can also regulate the localization of some lncRNAs. Some of the lncRNAs, which localize to the cytoplasm are processed similar to mRNA and transported out of the nucleus, while others with only one or very few exons are transported through the nuclear RNA export factor 1 (NXF1) [21].

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4. Functions of lncRNAs

Although lncRNAs are being studied for the last two decades, still sufficient information needs to be gathered as compared to other non-coding RNAs. However, recent researches show that it has a role in multiple biological processes. It has been shown to function at multiple levels including regulation at the transcriptional and post-transcriptional level, structural function, and had roles at the level of genome integrity. Here, we are going to describe the role of a few well-studied lncRNAs in little detail and tabulate different lncRNAs with their known functions. The lncRNAs functions can be understood in the following ways:

4.1 Regulation at transcriptional level

To understand the regulatory role of lncRNAs at the transcription level, it is best to use the example of well characterized lncRNA, Xist, which is most studied among others. Xist is a ~ 17 kb long lncRNA, which is synthesized and expressed from X-chromosome (inactive state) and represses the gene expression through PRC1 and PRC2 [22, 23, 24, 25]. As we all are aware that the female mammals carry a pair of X chromosome, while males carry single X chromosome, therefore one of the X chromosome is inactivated in females during early developmental events to ensure the dosage compensation between the two genders and Xist plays an important role in the process of X Chromosome Inactivation (XCI) [26]. Xist helps in maintaining the 3-D conformation of the X-chromosome such that it appears to be fully compact and maintains its inactive state (Xi) i.e. heterochromatin structure [26]. When Xist gets depleted from the chromatin, the inactive state of the X-chromosome gets its active state (Xa) by the process of X chromosome reactivation (XCR) which is not completely understood. How exactly does Xist play its role is through various chromatin factors including BRG1 and cohesin get repelled from the inactive state of the X-chromosome, leading to the disruption of the topologically associated domain (TADs) and in turn preventing the formation of chromatin super loops [27, 28]. In order to make the inactive state (the higher-order heterochromatin structure) Xist accompanies PRC1, PRC2 (Polycomb Repressive Complexes), and SMCHD1 (Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1) [29]. Altogether, it regulates gene expression by recruiting epigenetic factors or functioning as a protein complex scaffold. Figure 3 represents the entire process diagrammatically.

Figure 3.

Regulatory roles of Xist. Xist inhibits the BRG1 and Cohesin, and recruits PRC1 and PRC2 to fold in compact form. Later it tethers with SMCHD1 to further compact the chromosome to form Xi. Adapted from [30].

HOTAIR, another lincRNA, which is found to work at transcriptional level. LincRNA, stands for long intergenic non-coding RNA, a sub class of long non-coding RNA (lncRNA). LincRNAs are transcribed from the intergenic regions of protein-coding genes. HOTAIR, one among many lincRNAs, is synthesized from the genomic region of HOXC gene and it is of ~2.2 kb in length. It controls the gene expression by modulating histone modification of target gene at HOXD loci [31]. The lincRNA binds to Polycomb Repressive Complex 2 (PRC2) and silence the transcription of HOXD loci [31, 32, 33]. The large number of lncRNAs are now discovered because of technological advancement and found to function as HOTAIR [10, 34, 35, 36]. It is also found to be associated with cancer and play important role in tumorigenesis, and metastasis [34].

There are many lncRNAs are listed in Table 1 that function similarly or differently at the transcriptional level and control the gene expression and cell fate. Some of the lncRNAs AIRN [80], ANCR [81, 82], ANRIL [37, 83, 84], BCAR4 [85] are nuclearly localized. AIRN functions at transcriptional level while remaining three controls the gene expression by modulating the histone modification.

FunctionlncRNAsInteracting PartnerMechanism of FunctionPatho-physiologyReferences
Regulation of TranscriptionANRILPRC1, PRC2Recruits PRC to the promoters of CDKN2A and CDKN2BCancer and other diseases[37, 38]
LINC-PINTPRC2Suppresses the gene expressionDown-regulated in many cancers[39]
lncPRESS1Sirtuin 6As decoy to regulate gene expressionESC differentiation[40]
XistPRC2, hnRNPK, YY1Inactivate gene on X-chromosomeCancer and development[41, 42, 43, 44, 45, 46]
TARIDGADD45AForms R-loopsDemethylation[47, 48]
UMLILOWDR5-MLLCXCL chemokines transcriptionTranscription of immune genes[49]
HOTTIPWDR5-MLLHOXA genesLeukaemogenesis[50, 51]
COOLAIRPRC2Histone H3 K27-me3Regulates flowering time[52, 53]
Post-transcriptional RegulationPNCTRPTBP1Inhibits splicingUpregulated in cancers[54]
PNUTSmir-205Upregulate ZEB1 & ZEB2, promote EMTEMT in Breast Cancer[55]
TINCRSTAU1RNA stability and expressionDysregulated in many cancers[56]
FAST𝛃-TrCPInhibit 𝛃-catenin degradation, activate WNT signalingPluripotency[13]
NKILAp65Inhibits NF-𝜿BSilencing of NKILA improves immune therapy[57]
Structural FunctionsNEAT1MALAT1Scaffold lncRNABreast and Skin cancers[58, 59, 60, 61, 62, 63]
MALAT1NEAT1, U1 snRNA, SR proteinSR protein phosphorylationExpressed in many cancers[58, 63, 64, 65, 66, 67, 68, 69, 70, 71]
sno-lncRNAsRBFOX2mRNA splicingPrader-Willi Syndrome[72]
Genome IntegritylincRNA-p21hnRNPKRepress p53 induced gene expressionDysregulated in many cancers[73, 74]
PANDANF-YARepress proapoptotic geneInhibits apoptosis and senescence[75]
NORADPumilio, RBMXPromote genomic stabilityDysregulated in many cancers[76, 77, 78, 79]

Table 1.

List of lncRNAs with their functions.

4.2 Regulation at post-transcriptional level

There are lncRNAs which control the gene expression at post transcriptional levels. Here, PNUTS lncRNA serve the purpose to understand the mechanism they use. PNUTS is also known as PPP1R10, which generates mRNA, but alternative splicing leads to the synthesis of PNUTS lncRNA. This lncRNA actually functions as sponge and have binding sites for mir-205, which has been shown to bind ZEB1 and ZEB2 mRNA and causes the degradation of ZEB1 and ZEB2 mRNA. ZEB1 and ZEB2 are well known transcription factors associated with epithelial-mesenchymal transition [55]. In normal condition, the level of ZEB1 and ZEB2 is regulated by mir-205, but in cancer condition, when PNUTS lncRNA level goes up, mir-205 competitively binds to the lncRNA and becomes unavailable to their target ZEB1 and ZEB2, therefore it cannot degrade ZEB1 and ZEB2 mRNA, ultimately leading to the high level of ZEB1 and ZEB2 transcription factors. In turn, EMT proceeds and cancer progresses. Figure 4 illustrates the role of PNUTS as post-transcriptional regulator of gene expression. This lncRNA does not affect the transcription process, but it does regulation of gene expression through microRNA-sponge function [55].

Figure 4.

PNUTs as miRNA sponge. Regulation of Zeb1 and Zeb2 expression at post-transcriptional level. The level of PNUTS affect the EMT process. In cancer cells, PNUTS is expressed at high level and functions as miRNA sponge to bind miR-205 which targets ZEB1 and ZEB2, and EMT proceeds. In normal cells miR-205 binds to ZEB1 and ZEB2 and degrade them, ultimately results in No EMT progression.

MALAT1 stands for Metastasis-associated lung adenocarcinoma transcript 1, also known as Nuclear Enriched Abundant Transcript 2 (NEAT2). It is ~8 kb long and transcribed from single exon [86]. As the name suggests, MALAT1 was first identified as metastasis associated lncRNA in non-small cell lung cancer (NSCLC) and was used as prognostic marker for NSCLC patient [87]. MALAT1 plays important role in splicing of mRNA. It interacts with serine-arginine splicing factor (SR protein) and governs the distribution of various splicing factors in nuclear speckle domain. It maintains the phosphorylated SR proteins level and changes in the level of MALAT1 affect the alternate splicing of endogenous mRNAs [88].

There are many other lncRNAs (See the Table 1), which work similar to PNUTS lncRNA and control the expression of different genes and control many biological processes.

4.3 Structural roles of lncRNAs

MALAT1 is so far well characterized lncRNA. The lncRNA has been shown to function at different levels including transcriptional where it facilitates the transcription factor binding to the promoters, can be part of splicing regulation, can regulate the gene expression epigenetically by interacting with PRC2 components namely EZH2, EED and SUZ12 to block miRNA or other gene expression usually through trimethylation at lysine 27 of histone H3 [89]. The lncRNA can be used as biomarkers and this can be chosen for targeted drug therapy. MALAT1 also functions as sponge for miR-1 binding and found to be engaged in the development of bone and joint diseases [90]. MALAT1 functions as miRNA sponge and captures miR-1, which is associated with Cx43 repression and OPLL (Ossification of the posterior longitudinal ligament). Figure 5 represents the explained roles of lncRNA MALAT1.

Figure 5.

Regulatory roles of MALAT1. MALAT1 (~8.7kb IcnRNA, single exon) governs the distribution of splicing factors and play an important role in alternate splicing (a). It also control the gene expression via epigenetic machinery using PRC2 (b). It regulates the transcription (c) and can effectively trap miRNAs as sponge (d).

4.4 Other roles of lncRNAs

lncRNAs have been shown to perform various function. It interacts with all major biomolecules such as DNA, RNA, and proteins and modulate chromatin remodeling, expression of neighboring (adjacent or nearby) or distant genes. It can also affect RNA splicing, RNA stability and translation [91]. It directly interacts with DNA to form R-loop or RNA DNA triplex (RNA: DNA: DNA loop). It functions to control and regulate the gene expression at chromatin level to modulate the histone modification and activation or repression of gene. It also functions as sponge to capture multiple miRNAs and ultimately governs the expression of genes [92]. It also functions in rRNA maturation in mitochondria, a lncRNA RMRP is a part of mitochondrial RNA processing endoribonuclease (MRP) and carry out the maturation of rRNA [93].

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5. Conclusions

lncRNAs are a comparatively new class of non-coding RNA, which has been shown to execute many biological functions. The lncRNA genes can be found anywhere in the genome e.g. intronic, overlapping, anti-sense, or stand-alone. It has been shown to perform many biological functions including a regulatory role in controlling gene expression. This sub-class of ncRNAs is tissue-specific and often shows differential expression patterns in diseases including cancers and heart diseases. These lncRNAs can be utilized as biomarkers as well as for targeted therapy. They function to regulate gene expression at various levels such as transcriptional and post-transcriptional as well as structural. It also functions as a sponge for miRNAs binding and adds another way of regulating gene expression. They may be a key player in cancer progression. It needs further investigations to find its involvement in other biological functions. This will help us to move forward from considering junk to useful biomolecules. The current understanding of lncRNA biology is somewhat limited, which will be further discussed and elaborated on in the future.

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Acknowledgments

I would like to express my sincere thanks to the Indian Institute of Technology Dharwad for providing all the necessary facilities and access to different journals. I am thankful to Paula Gavran for her help and assistance throughout the submission of this chapter.

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Conflict of interest

The authors declare no conflict of interest.

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Authors’ contribution

PK drafted the chapter, edited the figures as per reviewers’ comments and suggestions. NB drew the figures. The authors read and approved the chapter for submission.

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Written By

Pranjal Kumar and Nikita Bhandari

Submitted: 22 February 2022 Reviewed: 12 April 2022 Published: 09 June 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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