Long Telomeric Repeat-Containing RNA: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Maria Grazia Andreassi.

Telomere dysfunction is implicated in vascular aging and shorter leucocyte telomeres are associated with an increased risk of atherosclerosis, myocardial infarction, and heart failure. Another pathophysiological mechanism that explains the causal relationship between telomere shortening and atherosclerosis development focuses on the clonal hematopoiesis of indeterminate potential (CHIP), which represents a new and independent risk factor in atherosclerotic cardiovascular diseases. Since telomere attrition has a central role in driving vascular senescence, understanding telomere biology is essential to modulate the deleterious consequences of vascular aging and its cardiovascular disease-related manifestations. Emerging evidence indicates that a class of long noncoding RNAs transcribed at telomeres, known as TERRA for “TElomeric Repeat-containing RNA”, actively participates in the mechanisms regulating telomere maintenance and chromosome end protection. However, the multiple biological functions of TERRA remain to be largely elucidated. 

  • TERRA
  • telomere
  • clonal hematopoiesis of indeterminate potential vascular aging

1. Long Telomeric Repeat-Containing RNA (TERRA) Transcription

Until 2007, telomeres were assumed to be transcriptionally silent due to their heterochromatic state and low gene density. Subsequently, it was discovered that RNA polymerase II initiates transcription in subtelomeric regions to produce the evolutionarily conserved long noncoding TERRA in mouse and human cells [5[1][2],27], changing the previous view and stimulating new research in the telomere field [28,29,30][3][4][5]. Later, it was shown that TERRA is expressed in many other species, demonstrating its conservative nature [28,29,30][3][4][5]. TERRA transcription begins from the subtelomeric region in the 5′ to 3′ direction (from the centromere to telomere) and proceeds to the end of chromosomes within the telomeric repeats (Figure 1).
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Figure 1. Illustration of the biogenesis of TERRA generated via transcription. The black arrow indicates the direction of transcription by RNAPII from the subtelomeric sequences (61-29-37 repeats TERRA promoter) into the telomeric tract. TERRA transcripts are indicated as soluble or stabilized G-quadruplex structures.
Subtelomeric CpG islands, consisting of three different repetitive DNA sequences known as “61-29-37 bp repeats”, are thought to act as TERRA promoters and binding sites for the chromatin organizing factor CTCF (CCCTC-binding factor), which acts as a key regulator of TERRA expression [31][6]. TERRA transcripts are heterogeneous in length, ranging anywhere from 100 bases up to 9 kilobases in length for human cells, consist of both subtelomeric-derived sequences and a G-rich telomeric repeat tract with an average length of 200 bases, and they may be stabilized by a G-quadruplex forming at the displaced G-rich DNA strand. TERRA is mostly detected in nuclear cellular fractions, where they colocalize with telomere in the form of RNA-DNA hybrid R-loop [28,29,30][3][4][5]. TERRA 5′ ends are capped by 7-methyl-guanosine cap structures and rarely (~10%) polyadenylated at their 3′. This polyadenylation influences TERRA stability and localization, supporting the notion that different fractions may have different functions [28,29,30][3][4][5]. Non-polyadenylated TERRA mainly localizes to telomeres, while polyadenylated TERRA is found in the nucleoplasm, exhibiting a much longer half-life than the non-polyadenylated form with a half-life of 8 to less than 3 h, respectively [28,29,30][3][4][5]. Moreover, it has been also shown that TERRA is regulated in a cell-cycle-dependent manner in human cells. TERRA levels are higher in G1 and progressively decline upon entry into the S phase of the cell cycle, reaching the lowest levels in the late S/G2 phase, a time that roughly corresponds to telomere replication [28][3]. Additionally, Feretzak and colleagues demonstrated that TERRA is expressed from different chromosome ends and in a variety of normal and several cancerous human cell lines by using real-time RT-PCR quantification [32,33][7][8]. Both the subtelomeric-derived sequence and telomere-derived TERRA can be analyzed via RT-qPCR using specific primers, allowing one to distinguish the chromosome of origin of a TERRA transcript, although some chromosomes have highly similar subtelomeric sequences (Figure 2).
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Figure 2. A scheme of TERRA analysis by qRT-PCR. After RNA isolation, TERRA-specific primers can generate a pool of TERRA cDNA molecules with diverse subtelomeric sequences. By using PCR-specific primer pairs, it is possible to amplify the subtelomeric sequence from each chromosome from the pool of transcribed TERRA cDNA.

2. Biological Functions of TERRA

Recent observations support the notion that TERRA sustains multiple functions at telomeres, as has been extensively reviewed [29,30,34,35,36,37][4][5][9][10][11][12]. However, the complex biological functions of TERRA and the specific mechanisms by which TERRA contributes to telomere biology remain largely elusive. At present, TERRA is generally believed to play a role in the protection of telomeres, the regulation of telomere length and telomerase activity, as well as in the formation of heterochromatin at the ends of chromosomes [29,30,34,35,36,37][4][5][9][10][11][12]. Regarding TERRA’s interaction with telomerase, it can act as a negative regulator of telomerase activity in cells with long telomeres, while functioning as a positive regulator of telomerase activity at short telomeres [36][11]. In the presence of long telomeres, TERRA may act as a negative regulator of telomerase activity by acting through the base pairing of the tandem repeats found throughout TERRA’s 3′ end to the complementary RNA template region of the TERC region, and blocking telomerase binding to telomeric ssDNA [36][11]. Additionally, TERRA may also interact with the subunit hTERT as an allosteric inhibitor of telomerase function, abolishing the catalytic activity of adding further telomeric DNA repeats [36][11]. On the other hand, short telomeres may induce TERRA expression, which might represent a signal to recruit telomerase and perform subsequent telomere elongation [29,36][4][11].
Additionally, TERRA interacts with the shelterin complex, and its transcription is regulated by TRF1 and TRF2 [38,39,40][13][14][15]. Indeed, the G-quadruplex structure of TERRA is an important recognition element for the TRF2 shelterin subunit and physically interacts with it to bind to telomeric DNA and also with TRF1 to preserve the telomere’s structural stability [38,39,40][13][14][15]. By interacting with RNA polymerase II, TRF1 seems to positively regulate TERRA expression levels, while telomere dysfunction induced by the depletion of TRF2 leads to increased TERRA levels at all transcribed subtelomeres [38,39,40][13][14][15]. Moreover, long non-coding RNAs are known to mediate epigenetic changes on chromatin by functioning as recruiters for chromatin-modifying enzymes to genomic loci [29][4]. Accordingly, TERRA is thought to play a similar role, recruiting both heterochromatic proteins (H3K9me3 and HP1 proteins) and the associated chromatin-remodeling complexes to telomeres, such as NoRC (nucleolar remodeling complex), MORF4L2 (a component of the NuA histone acetyltransferase complex), and ARID1A (a component of the SWI/SNF nucleosome remodeling complex); this contributes to establishing or maintaining heterochromatin formation [29,39][4][14]. Figure 2 summarizes the key biological functions proposed for TERRA as a key regulator of telomere maintenance and heterochromatin formation in telomeres.
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Figure 2. Overview of the main functions of TERRA. (a) For long telomeres (left), TERRA can bind to telomerase, repressing its activity; when a telomere is critically short (right), the repression of TERRA expression is removed. (b) TERRA interacts with shelterin proteins by enhancing chromosome-end protection with secondary protective structures, including G-quadruplexes; (c) TERRA contributes to maintaining heterochromatin formation via the recruitment of chromatin proteins.

3. Dysregulation of TERRA in Human Studies

The study of TERRA dysregulation may be particularly relevant to the development and progression of several diseases in which telomere dysfunction is present. The first evidence of TERRA expression in humans comes from patients with facial anomalies syndrome (ICF), a rare autosomal recessive immune disorder caused by mutations in the DNA methyltransferase 3 [41][16]. Primary fibroblasts from ICF patients have shown hypo-methylated TERRA subtelomeric promoters and increased levels of TERRA, suggesting that this dysregulated expression may explain the abnormally short telomeres and cell senescence in ICF patients [41][16]. Several studies have shown the dysregulation, mainly the downregulation, of TERRA in various human cancer tissues compared with normal tissues [42,43,44,45,46,47,48][17][18][19][20][21][22][23]. 
Table 1.
Summary of human studies with TERRA expression profile and dysregulation.
Reference Human Model Study Design Biological Sample Method Main Findings
Sampl S et al., 2012 [42][17] Astrocytoma Cancer tissue Tissue Real-Time PCR Down-regulation
Vitelli V et al., 2018 [43][18] Head and neck squamous cell carcinoma Healthy tissue/Cancer tissue Tissue Real-Time PCR Down-regulation
Adishesh M et al. 2020 [44][19] Endometrial cancer Healthy tissue/Cancer tissue Endometrial biopsy Real-Time PCR Down-regulation
Bae SU et al., 2019 [45][20] Colorectal cancer Cancer tissue Tissue Real-Time PCR Up-regulation
Storti CB et al., 2020 [46][21] Non-small cell lung cancer Healthy tissue/Cancer tissue Tissue Real-Time PCR Up-regulation
Cao H et al., 2020 [47][22] Hepatocellular carcinoma Healthy tissue/Cancer tissue Tissue FISH Down-regulation
Manganelli M et al., 2022 [48][23] Hepatocellular carcinoma Healthy tissue/Cancer tissue Case/Control Tissue Plasma Real-Time PCR Down-regulation in tissue

Up-regulation in plasma
Wang Z et al., 2015 [49][24] Cancer Case/Control Plasma RNA Seq Up-regulation
Gao Y et al., 2017 [50][25] Idiopathic pulmonary fibrosis Case/Control Blood Real-Time PCR Up-regulation
Diman A et al., 2016 [51][26] Healthy runners Pre/post exercise tissue Muscle biopsy FISH Up-regulation
Chang KV et al., 2020 [52][27] Sarcopenia Case/Control Leukocytes Real-Time PCR Down-regulation
Recently, a cell-free form of TERRA (cfTERRA) was also found to be a component of extracellular microvesicular exosomes in cancer cell culture and human blood plasma, as damage signals mediating the crosstalk between telomere dysfunction and inflammatory cytokines can lead to the activation of inflammation in the tissue microenvironment [49][24]. In addition, TERRA expression levels significantly increased in the peripheral blood mononuclear cells of patients with idiopathic pulmonary fibrosis (IPF) and were inversely correlated with force vital capacity (FVC%).

4. TERRA Expression and Vascular Biology

Although it is well documented that telomere dysfunction is involved in vascular and cardiac cell senescence [1,2[28][29][30][31],3,4], the role of TERRA in vascular biology is surprisingly unknown. To date, no study has investigated the association between the TERRA expression profile and cardiovascular diseases, especially for the clinical conditions in which there is strong evidence of the relationships between telomere shortening and increased risk, such as coronary atherosclerosis, myocardial infarction, ischemic heart disease, and stroke [14,15,16,17,18,19,20][32][33][34][35][36][37][38]. Understanding TERRA transcription dynamics and its involvement in telomere biology may have a clear potential impact on clinical practice and the potential development of effective targeted vascular aging therapies. Indeed, therapeutic approaches to modulate the telomere system are considered as promising alternative treatments for cardiovascular pathologies [53,54][39][40]. The induction of telomerase activity, either after the reactivation of endogenous TERT expression, is considered a prime target in the development of potent therapeutics against vascular aging and cardiovascular disease [55][41]. Enhanced TERT activity can induce beneficial and protective effects through the canonical pathway against telomere shortening and the excessive senescence of vascular cells. Activating the non-canonical functions of TERT may protect mitochondrial function from antagonizing oxidative stress, DNA damage, and apoptosis [55][41]. Experimental evidence supporting this notion shows the therapeutic potential of enhancing the telomerase activity for cardiovascular disease [56,57][42][43]. For instance, telomerase gene transfer therapy improved ventricular function and prevented heart failure after acute myocardial infarction in mouse models [56][42]. Additionally, the use of the telomerase activator TA-65, a natural plant compound, has been reported to up-regulate telomerase activity and elongate telomeres without increasing cancer incidence [57][43]. However, despite these interesting results in preclinical models of aging and disease, the overexpression of TERT may have anti-apoptosis and cell immortalization effects, potentially increasing the risk of cancer [58][44]. The development of safe strategies in which telomerase is induced temporarily and selectively in aged cells without promoting off-target effects is essential to clarify its potential as a therapeutic target. One attractive application is the use of RNA-centered approaches specifically directed to TERRA and TERC, including RNA interference, antisense oligonucleotides and small molecules [59][45]. For instance, several studies have shown that drugs targeting TERRA molecules could be promising therapeutic strategies against cancer. For instance, TERRA expression in human cancer cells could also be regulated by demethylating agents and histone deacetylase inhibitors, such as 5-azacytidine and trichostatin [60,61][46][47]. Moreover, stabilizing the G4 structures of TERRA by using small-molecule ligands (e.g., BRACO-19, Telomestatin) may be one of the most promising approaches to inhibiting telomerase and hence inhibiting the proliferation of cancer cells and tumor growth [60,61][46][47]. Indeed, a recent in vitro and in vivo studies have shown that targeting TERRA using hit 17, a small molecule that can bind and stabilize the G4 conformation, could represent a promising strategy for a novel therapeutic approach to multiple myeloma [62][48]. Additionally, the use of a telomeric antisense oligonucleotide has been recently shown to selectively inhibit the DNA damage response in telomeres in both cells and mice, reducing the markers of cellular senescence apoptosis and the expression of SASP cytokines, as well as improving health and lifespan in an animal model [63,64][49][50]. Thus, studying the dynamics of TERRA and the antisense approach to targeting specific targets in human vascular cells and in vivo models may unveil unexpected functions for delaying vascular aging and also provide cardioprotection.

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