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Regulation of Genes by Non-Coding DNA and the Discovery of Regulatory Elements

The majority of the DNA is non-coding apart from a small percentage of it consisting of protein-coding genes. Non-coding DNA is not capable of providing instructions that generate proteins; it was once assumed by scientist and researchers that non-coding DNA is “junk” and does not have any function. This perspective changed when it was discovered that non-coding DNA possess sequences that play a regulatory role in the activation and suppression of genes (1). These were known as regulatory elements that provided site for specialised proteins called transcription factors binding and repress or activate transcription. When the regulatory elements fail to repress the process of transcription, it leads to the production of long non-coding RNAs (lncRNAs) upon extensive transcription of the genomes. Long non-coding RNAs are ribonucleic acids that are longer than 200 nucleotides and do not get translated to form functional proteins (1). Nevertheless, evidence gained through several research over the course of time has shown that long non-coding RNAs have a crucial role in the regulation of genes and are extensively expressed. Recent research has been focused on decoding the biogenesis of lncRNAs and the areas where its generation differs from the production of mRNAs. Progress has been made in identifying the distinction as being related to the function and subcellular localizations of the lncRNAs. It was found that based on the location of the lncRNAs, they are capable of regulating the function and assembly of membrane-less nuclear bodies, modulating chromatin function, interfering with signalling pathways and altering the translation and stability of cytoplasmic RNAs (2). The following review will focus on the various roles of long non-coding RNAs that have been reported by recent research and will explore the various findings that have been identified by scientists.

The characteristics and functions described by a group of researchers identified that majority of the long non-coding RNAs were transcribed by RNA polymerase II through the utilization of the same splicing signals as the protein-coding genes and these undergo posttranscriptional modification at the 5’ and 3’ ends in a similar manner (3). However, they reported that the long non-coding RNAs have less exons than mRNAs and are also shorter in length than the latter. Moreover, they also found that the long non-coding RNAs were not as conserved as the mRNAs despite the probable similarity in in function. A recent study focused on the single-cell analysis of long non-coding RNAs, explored by the researchers of this paper found that individuals cells abundantly expressed the RNA in contrast to the studies focused on bulk tissue expression. This was suggestive of the fact that analysis of whole tissues is in reality the accumulation of average expression signals by different types of cells which therefore, decreases the actual patterns of expression in individual cells (3). The researchers reported that long non-coding RNAs play a role in the regulation of gene expression that was already established by previous studies, in addition, they also reported that this RNA type had a role in the maintenance of pluripotency, genomic imprinting, compartmentalization and organization of nucleus and the process of alternative splicing. The researchers reported that on the basis of their function, lncRNAs can be classified into four major types such as (a) signal lncRNAs that function as transcription regulators in the presence of specific stimuli, (b) scaffold lncRNAs, that function as the host platforms for molecular complex formation, (c) decoy lncRNAs, function as regulators of transcription through binding and sequestration of protein targets and do not perform any other role and lastly, (d) guide lncRNAs that bind and direct proteins to specific genomic loci. Moreover, the researchers also focused on the additional role of lncRNAs in their paper through describing its interaction with miRNAs to influence the latter’s activity and expression. It was an exceptional finding reported by the researchers of this paper, as this mechanism provided evidence of interaction between the miRNA-lncRNA that acts as an additional mechanism of regulation of transcription within cells. In addition, diseases associated with the lncRNAs have been reported to be above 200. Specifically, the involvement of lncRNAs has been studied in three specific diseases- type II diabetes, Alzheimer’s disease and hepatocellular carcinoma. Similarly, another group of researchers explored the role of long non-coding in the common form of liver cancer known as hepatocellular carcinoma (4). Their study was focused on the role of long non-coding RNAs in the cancer which was a different approach than the previous studies that focused on the protein-coding genes as they played central role in regulating the biological process that is involved in the disease. They reported that previously considered junk non-coding RNAs such as long non-coding RNAs have an important function in the pathological and physiological processes involved in the disease (4). The paper reported on the first discovery of the role of lncRNAs that was made in the year 1990, where the lncRNA H19 played a role in restricting the growth of the organ through decreasing the expression of IGF2 which was identified in the liver tissue of a foetus. In the following year, the role of lncRNA XIST in carrying out the inactivation of X chromosome was discovered. Furthermore, the authors described the role of lncRNAs as the modulator of chronic liver diseases and the microenvironment in the liver. The paper suggested that lncRNA function as modulators of immune response, redox signalling and liver regeneration that play important roles in the regulation of the microenvironment of the liver and the chronic diseases of the organ. The researchers described that the dysregulation of the long non-coding RNAs in the abovementioned processes result in oxidative stress, outgrowth of the organ and chronic hepatitis that eventually initiate and lead to the progression of the hepatocellular carcinoma. The researchers explored the involvement of the lncRNAs in the viral infection and immune response where the virus-induced lncRNAs were able to promote the proliferation of the cells or suppress the immune response of the host that results in the chronic infection and the formation of the hepatocellular carcinoma in the host. The lncRNAs signal the liver regeneration in response to the hepatectomy, it does so by being independent of loss of tissue that results in the overgrowth and hepatocellular carcinoma. The researchers also described the mechanism by which the lncRNAs activate HIF-1a that supports the survival of the carcinoma under hypoxic conditions. Lastly, the researchers noted the significance of the lncRNAs in the carcinoma hallmarks where the dysregulated lncRNAs through unique mechanisms promoted the carcinoma which led to each tumour stage having a corresponding phenotype. Moreover they also elaborated on the hallmarks that were identified as the prolonged proliferation because of the aberrant regulation of cell cycle progression or growth factor receptors/RTK signalling, dysregulation energetics that was induced by the reprogramming of metabolism in the cells, increased stemness that was a result of hyperactive CSC-associated signalling and the enhancement of the metastasis that was induced by the formation of additional vessels and overexpressed mesenchymal markers (4).  The paper successfully introduced the possible role of lncRNAs as a diagnostic tool for the disease stating that in combination with other molecules such as the existing biomarkers of the disease, lncRNAs could become a desired method of liver cancer diagnosis. Moreover, the lncRNAs could also serve as the target for novel drug interventions as it has more advantage than methods that target protein as the base-pairing would be simpler than developing a specific inhibitor that binds to the protein (4).

Characteristics and Functions of Long Non-Coding RNAs

Researchers of another paper were focused on the recent development in the cellular functions of lncRNAs in mammalian cells at the molecular level (5). Apart from the role of lncRNAs in the regulation of transcription, the researchers highlighted the role of this RNA type in chromatin remodelling, promoting the recruitment of chromatin modifiers, also its role in preventing the recruitment of these modifiers. The researchers stated that lncRNAs that are localized in the nucleus are also associated with the chromatin and take part in the remodelling either in the cis or trans sites. Moreover, the lncRNAs are also involved in the pathway of Xist-mediated XCI (X-chromosome inactivation). The lncRNAs are involved through recruiting the inactive X chromosome for the association with the lamin B receptor at the lamina of the nucleus and silencing transcription. The elaborate mechanism also includes other lncRNAs with similar characteristics that function as modulators of gene expression. The lncRNAs also act as decoys that prevent the interaction of chromatin modifiers or histone to the particular DNA loci. Myosin heavy-chain associated RNA transcripts or Mhrt are a cluster of nucleus-retained, alternatively spliced lncRNAs that originate from the antisense transcription of myosin heavy chain 7 gene. The Mhrt are responsible for protecting the heart from pathological hypertrophy through Brg1 antagonization that promotes the pathological cardiac hypertrophy. The Mhrt recruits Brg1 from genomic loci targeting by association with the domain of RNA helicase that it utilizes for binding DNA. This prevents the recruitment of chromatin modifiers (5). The researchers also reported on the role of lncRNAs in the cytoplasm through regulation of mRNA turnover in various ways. The lncRNAs are capable of regulating the stability of mRNA through association with miRNA. Moreover, the researchers reported that a recent study identified a more complex regulatory network that consists various different non-coding RNAs including the lncRNAs. The lncRNA Cyrano, facilitates the efficient destruction of miR-7 through the promotion of trimming and tailing of the 3’ end that induces the target-RNA-directed miRNA destruction that results in the accumulation of Cdr1 in the brain. In addition, lncRNAs also modulate the stability of mRNA through recruitment of proteins that degrade the mRNA, for example, the Alu-containing lncRNAs are responsible for activating Staufen-1-mediated mRNA decay in trans. Lastly, the paper noted the features of lncRNAs that presented the challenges in their analysis and the acknowledgement of recent research that enhanced the information on the function of lncRNAs (5). The research on the role of long non-coding RNAs in bladder cancer revealed that lncRNAs are involved in the malignant tumour of the urinary system (6). The long non-coding RNAs are expressed abnormally in bladder cancer and the researchers indicated that over 100 dysregulated long non-coding RNAs are present in the urinary system disease that function as regulators of cell cycle, proliferation, migration, invasion, metabolism and resistance of drug in the disease. The abnormally expressed long non-coding RNAs play a crucial role in the tumorigenesis, progression and prognosis of bladder cancer (6). Similar to the extensive mechanism described by the other researchers, the molecular mechanisms of the lncRNAs in bladder cancer were explored and the researchers found that the RNA interacts with proteins, DNA and RNA during the disease. In addition, they also reported that thirty six abnormally expressed lncRNAs are closely associated with several clinical characteristics of bladder cancer such as the size of the tumour, invasion, metastasis, resistance or sensitivity to the drugs for bladder cancer. Similar to other findings in the previous papers, the researchers explored the role of lncRNAs as biomarkers for bladder cancer such that it can be utilized in the monitoring, early diagnosis and prognosis of the disease (6). Two other studies explored the role of lncRNAs in the epigenetic regulation in cancer and regulation of p53 network (7,8). Long non-coding RNAs have been demonstrated in the study to play crucial roles in the epigenetic modification of chromatin structure through regulation of important genes in particular cancer cells (7, 8). The long non-coding RNAs were reported to be important regulators of biological results of p53 through regulating its activity. The paper identified that several lncRNAs that are regulated by p53 have been discovered to interfere indirectly or directly with the tumour surveillance programme of p53 and other regulatory networks. The paper reported that the lncRNAs that are not regulated by p53 interfere with the signalling networks to regulate the levels of p53 protein and the transcriptional activity. They were also reported to alter the function, terminate and maintain p53 at low levels that can be tolerated by normal cells. Unique signatures of chromatin have been reported to be associated with genes encoding lncRNAs that are remarkably different in cancer cells such as colorectal carcinoma. It was reported that clusters of lncRNAs were expressed uniquely in cells of ovarian cancer where varied metastatic potential were detected. The study recommended that future studies much focus on exploring the role of lncRNAs in regulation of chromatin through their association with different proteins. It also recommended that future studies must focus on the identification of regulatory mechanisms through which the RNAs act on p53 to further understand its activity and mechanisms of surveillance (7, 8).

Conclusion

In conclusion, the papers that were reviewed provided deep insight into the various roles of long non-coding RNAs such as their role in the regulation of transcription, their role in the nucleus, cytoplasm, and their involvement in the pathology and physiology of various types of cancer such as hepatocellular carcinoma, bladder cancer, ovarian cancer and the regulation of p53 that plays a key role in the surveillance of tumour. Furthermore, the recommendations made by researchers were also identified that would aid in better understanding of the role of RNAs that were once assumed to be non-functional or junk.

References

  1. Oo JA, Brandes RP, Leisegang MS. Long non-coding RNAs: novel regulators of cellular physiology and function. Pflügers Archiv-European Journal of Physiology. 2021 Nov 18:1-4.
  2. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nature Reviews Molecular Cell Biology. 2021 Feb;22(2):96-118.
  3. DiStefano JK. The emerging role of long noncoding RNAs in human disease. Disease Gene Identification. 2018:91-110.
  4. Huang Z, Zhou JK, Peng Y, He W, Huang C. The role of long noncoding RNAs in hepatocellular carcinoma. Molecular cancer. 2020 Dec;19(1):1-8.
  5. Yao RW, Wang Y, Chen LL. Cellular functions of long noncoding RNAs. Nature cell biology. 2019 May;21(5):542-51.
  6. Li HJ, Gong X, Li ZK, Qin W, He CX, Xing L, Zhou X, Zhao D, Cao HL. Role of long non-coding RNAs on bladder cancer. Frontiers in cell and developmental biology. 2021:1821.
  7. Jain AK. Emerging roles of long non-coding RNAs in the p53 network. RNA biology. 2020 Nov 1;17(11):1648-56.
  8. Chatterjee M, Sengupta S. Emerging roles of long non-coding RNAs in cancer. Journal of biosciences. 2019 Mar;44(1):1-4.
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