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Long non-coding RNA

Long non-coding RNAs (lncRNAs) are a diverse class of non-coding RNA transcripts longer than 200 nucleotides that lack significant protein-coding potential and are primarily transcribed by RNA polymerase II.^[1] These molecules, often spanning from hundreds to over 100,000 nucleotides, exhibit low sequence conservation across species but harbor conserved functional domains, such as repetitive elements in cases like the XIST lncRNA involved in X-chromosome inactivation.^[1] Unlike protein-coding messenger RNAs (mRNAs), lncRNAs typically undergo processing similar to mRNAs, including capping, splicing, and polyadenylation, though some lack poly(A) tails and localize to specific subcellular compartments like the nucleus or cytoplasm.^[2] Discovered in the 1990s through studies of imprinted genes like H19 and dosage compensation mechanisms like XIST, lncRNAs have since been cataloged extensively via projects such as GENCODE, revealing thousands of such transcripts in the human genome.^[2] They function predominantly as regulators of gene expression through diverse mechanisms, including chromatin modification, transcriptional interference, and post-transcriptional modulation of mRNA stability and translation.^[3] For instance, lncRNAs can act as scaffolds to recruit chromatin-modifying complexes, form RNA-DNA hybrids (R-loops) to influence replication or repair, or sequester proteins to alter signaling pathways.^[3] Biologically, lncRNAs are essential for processes such as embryonic development, cell differentiation, and maintenance of genomic stability, with examples like NEAT1 forming paraspeckles for nuclear organization and NORAD preventing chromosomal instability.^[3] Dysregulation of lncRNAs is implicated in numerous diseases, including cancers—where MALAT1 promotes metastasis—and neurodegenerative disorders, positioning them as potential biomarkers and therapeutic targets due to their tissue-specific expression patterns.^[3] Despite advances, challenges persist in elucidating their precise mechanisms, given their low phenotypic visibility in knockout studies and context-dependent functions, underscoring the need for standardized nomenclature and enhanced functional assays.^[1]

Fundamentals

Definition and Discovery

Long non-coding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides that lack significant protein-coding potential.^[1] This arbitrary length threshold distinguishes them from shorter non-coding RNAs, such as microRNAs or small nucleolar RNAs, while their non-coding nature is assessed through computational tools evaluating features like short open reading frames (typically fewer than 100 codons) and poor evolutionary conservation of potential coding sequences.^[4] Unlike protein-coding messenger RNAs (mRNAs), lncRNAs show minimal association with ribosomes and are primarily functional as RNA molecules rather than templates for translation.^[5] The discovery of lncRNAs began with isolated examples in the late 1980s and early 1990s, predating genome-wide studies. One of the first identified was H19, a maternally imprinted transcript reported in 1991, which encodes an abundant RNA during mouse embryonic development without an open reading frame.^[6] Similarly, the Xist RNA, essential for X-chromosome inactivation, was characterized in 1991 as a 15 kb nuclear transcript expressed exclusively from the inactive X chromosome in female mammals.^[7] These early findings highlighted lncRNAs' roles in imprinting and dosage compensation but were viewed as exceptions in a predominantly protein-coding transcriptome paradigm. A major shift occurred in the mid-2000s with high-throughput technologies that unveiled the non-coding transcriptome's scale. Tiling array experiments, such as those from the FANTOM consortium in 2005, detected thousands of unannotated transcripts across the mouse genome.^[8] RNA sequencing (RNA-seq) further accelerated discoveries from 2008 onward, identifying pervasive transcription beyond protein-coding genes and confirming lncRNAs' ubiquity in eukaryotic cells. Nomenclature evolved alongside these advances, initially focusing on genomic context; the term "large intergenic non-coding RNAs" (lincRNAs) was coined in 2009 for intergenic transcripts longer than 200 nucleotides.^[9] By the early 2010s, the broader "lncRNA" designation encompassed diverse classes, including antisense and intronic types, as recommended by bodies like the HUGO Gene Nomenclature Committee.^[10] The ENCODE project's 2012 GENCODE v7 annotation established rigorous criteria for lncRNA identification, requiring evidence of transcription, polyadenylation, and absence of protein-coding capacity via tools like ribosome profiling and mass spectrometry. This framework emphasized functional annotation over mere length, prioritizing transcripts with biochemical signatures akin to mRNAs but without translational output.^[11]

Abundance and Diversity

Long non-coding RNAs (lncRNAs) represent a substantial fraction of the eukaryotic transcriptome, with estimates indicating that they comprise over 68% of annotated genes in deep-sequencing surveys of the human polyadenylated (polyA+) RNA fraction.^[12] In humans, conservative annotations from GENCODE release 49 (2025) identify 35,899 lncRNA genes, producing 191,079 transcripts, while broader catalogs such as NONCODE v6.0 (updated 2021) document around 173,112 human lncRNA transcripts, highlighting the variability in detection and annotation approaches.^[13]^[14] These numbers underscore that lncRNAs may outnumber protein-coding genes, potentially exceeding 100,000 loci when including unannotated or lowly expressed variants, though many remain uncharacterized due to challenges in distinguishing them from transcriptional noise or degraded mRNAs.^[1] LncRNAs exhibit considerable diversity in their genomic organization and expression profiles. Based on their positional relationship to protein-coding genes, they are broadly categorized as intergenic (also known as lincRNAs), antisense, intronic, and enhancer-associated, with intergenic lncRNAs often residing in regions between genes and antisense types overlapping the opposite strand of coding loci.^[1] Expression-wise, lncRNAs display higher tissue specificity than mRNAs, with studies reporting that up to 70% of lncRNAs are restricted to specific tissues or cell types compared to about 40% for protein-coding transcripts, reflecting their roles in fine-tuned regulatory networks during development and homeostasis.^[15] This variability is further evident in their sequence features, where lncRNAs generally have lower sequence conservation and fewer exons than mRNAs, contributing to their functional plasticity. Across eukaryotes, lncRNA abundance scales with organismal complexity, with humans harboring over 100,000 predicted lncRNAs compared to far fewer in simpler models like yeast (Saccharomyces cerevisiae), where only hundreds of stable lncRNAs have been identified despite pervasive transcription covering 75-85% of the genome.^[1]^[16] Recent advances in long-read RNA-seq and direct RNA sequencing (2023-2024) have doubled estimates of lncRNA diversity in non-model organisms, such as plants, revealing thousands more transcripts in species like Arabidopsis and crops, often linked to stress responses and development.^[17]^[18] Despite these insights, annotation remains incomplete, as databases like NONCODE continue to expand with experimentally validated entries, emphasizing the need for improved computational tools to resolve the full spectrum of lncRNA repertoires.^[14]

Biogenesis and Properties

Transcription and Processing

Long non-coding RNAs (lncRNAs) are primarily transcribed by RNA polymerase II (Pol II), similar to protein-coding messenger RNAs (mRNAs), with the vast majority of annotated lncRNA loci showing Pol II occupancy and associated chromatin marks such as histone H3 lysine 4 trimethylation (H3K4me3) at promoters and H3K36me3 in gene bodies.^[3] This Pol II-dependent transcription enables lncRNAs to undergo co-transcriptional processing akin to mRNAs, although a small subset of lncRNAs is transcribed by RNA polymerases I or III, such as certain intergenic transcripts derived from rDNA repeats or Pol III-driven elements like Alu-derived lncRNAs.^[1] LncRNA promoters often exhibit bidirectional activity, co-transcribing with nearby protein-coding genes in convergent or divergent orientations, which can influence local chromatin architecture and gene expression.^[1] Additionally, many lncRNAs arise from enhancer regions, where divergent transcription from bidirectional enhancers produces unstable enhancer RNAs (eRNAs) that can mature into longer lncRNA forms, contributing to regulatory feedback loops.^[3] Following transcription initiation, lncRNA precursors undergo canonical processing steps that mirror those of mRNAs, including 5' capping with a 7-methylguanosine (m7G) cap shortly after Pol II initiation, which protects the transcript from exonucleases and facilitates subsequent maturation.^[19] Splicing removes introns via the spliceosome, with most lncRNAs being multi-exonic and featuring an average of ~2 exons (thus ~1 intron) per transcript, fewer than typical mRNAs, though intron lengths are typically longer than in mRNAs, leading to inefficient or retained splicing in some cases.^[20] At the 3' end, cleavage and polyadenylation occur at polyadenylation sites (PAS), resulting in many lncRNAs being polyadenylated (polyA+), similar to mRNAs, while others are polyA- and often more nuclear-retained, due to variability in polyadenylation signals.^[1] Mature polyA+ lncRNAs are exported to the cytoplasm via the TAP/NXF1 (also known as Mex67-Mtr2 in yeast) heterodimer, which binds the polyA tail through adaptor proteins like the TREX complex, facilitating translocation through nuclear pore complexes.^[21] LncRNA maturation exhibits notable variations that distinguish it from mRNA processing, including instances of unspliced transcripts that retain introns and function in the nucleus, such as certain stress-responsive lncRNAs that evade full splicing due to weak splice sites.^[22] Although circular RNAs (circRNAs) form via backsplicing and are considered a distinct class, some lncRNAs may form stable secondary structures that mimic looped conformations, enhancing stability in specific contexts. Studies have highlighted Pol II pausing and termination as key factors in lncRNA biogenesis; for example, promoter-proximal pausing mediated by the NELF complex allows co-transcriptional regulation, while termination dynamics can generate isoform diversity beyond standard mRNA pathways.^[3] Aberrant lncRNA transcripts, such as those with improper capping, splicing defects, or failed polyadenylation, are subject to rigorous quality control mechanisms to prevent accumulation of dysfunctional RNAs. The 5'-3' exonuclease XRN2 plays a central role in degrading these aberrant species co-transcriptionally or shortly after release from Pol II, often in coordination with surveillance factors like the exosome complex, thereby maintaining genomic stability and preventing interference with normal gene expression.^[23] LncRNAs exhibit half-lives comparable to mRNAs, averaging around 10-15 hours depending on subcellular location, though some studies report medians of ~3-5 hours for specific subsets, reflecting variable turnover via pathways like XRN2-mediated decay.^[24] ^[25] This variability, measured via genome-wide metabolic labeling, contrasts with the more stable profiles of housekeeping mRNAs and highlights lncRNAs' adaptation for dynamic cellular responses.^[25]

Structure and Stability

Long non-coding RNAs (lncRNAs) often adopt complex secondary structures characterized by stem-loops, hairpins, and modular domains that contribute to their functional architectures. These elements are predicted computationally using tools like RNAfold, which employs thermodynamic models to forecast stable folding patterns based on base-pairing probabilities. For instance, the lncRNA HOTAIR exhibits an intricate secondary structure comprising multiple hairpins and repeat motifs, including a 300-nucleotide domain with tandem stem-loops that facilitate modular interactions.^[26] Such structural motifs enhance the specificity of lncRNA recognition by binding partners, as demonstrated by mutagenesis studies altering stem lengths and loop sizes in HOTAIR.^[27] Beyond secondary folding, lncRNAs engage in tertiary interactions that stabilize higher-order conformations, particularly through associations with RNA-binding proteins (RBPs). Heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP A2/B1, bind to specific motifs in lncRNAs like HOTAIR, promoting compact tertiary structures via multivalent contacts that bridge distant RNA domains.^[28] Additionally, lncRNAs such as NEAT1 drive phase separation into membraneless organelles like paraspeckles by forming dynamic RNA-protein networks; NEAT1's modular domains, including repeat-containing regions, nucleate aggregation with RBPs like NONO and SFPQ, resulting in liquid-like condensates that sequester cellular components.^[29] These interactions underscore the role of lncRNA tertiary architecture in compartmentalizing nuclear processes.^[1] The stability of lncRNAs is modulated by sequence elements and protein interactions that influence their degradation and subcellular persistence. AU-rich elements (AREs) in lncRNA transcripts promote rapid decay by recruiting decay factors, similar to their role in mRNAs, though lncRNAs generally exhibit variable half-lives due to processing differences.^[30] Stabilizing RBPs like HuR counteract this by binding AU-rich or cytosine-rich stretches; for example, the lncRNA HMS recruits HuR to its target sites, delaying exonucleolytic degradation and extending transcript lifespan.^[31] Furthermore, many lncRNAs display prolonged nuclear retention compared to cytoplasmic mRNAs, attributed to weak splice site motifs and interactions with nuclear RBPs that hinder export, thereby maintaining higher steady-state levels in the nucleus.^[32] Structural studies, including imaging techniques, have revealed conformational flexibility in lncRNA-RBP complexes like NEAT1 in paraspeckles.^[1] As of 2025, genome-wide studies continue to refine lncRNA annotations, highlighting roles of additional modifications like pseudouridine in modulating structure and function.^[33] Concurrently, investigations into epitranscriptomic modifications demonstrate that N6-methyladenosine (m6A) marks subtly alter lncRNA folding by disrupting base stacking in stems, leading to more open conformations that influence RBP affinity and stability, as observed in thermodynamic analyses of m6A-modified lncRNAs like MALAT1.^[34]^[35]

Genomic Organization

Location and Architecture

Long non-coding RNAs (lncRNAs) are transcribed from diverse genomic contexts, including intergenic regions, where they are classified as long intergenic non-coding RNAs (lincRNAs), as well as genic regions involving intronic and exonic overlaps with protein-coding genes.^[36] Antisense lncRNAs, transcribed from the opposite strand of protein-coding genes, represent another major category, often overlapping with sense transcripts.^[37] A substantial proportion of lncRNA loci, estimated at around 20-40% in various annotations, are associated with regulatory elements such as enhancers and promoters, reflecting their potential integration into gene regulatory networks.^[38]^[1] LncRNA loci exhibit distinctive architectural features that mirror those of protein-coding genes, including the presence of bidirectional promoters that drive divergent transcription from shared regulatory elements.^[39] These loci are frequently enriched within topologically associating domains (TADs), self-interacting chromatin regions that compartmentalize the genome, with lincRNA promoters often positioned relative to orthologous genes in syntenic blocks across species.^[40] Clustering of lncRNA genes in syntenic regions underscores their positional conservation, facilitating coordinated regulation within chromatin loops.^[41] From an evolutionary perspective, lncRNA architectures arise through mechanisms such as tandem duplications, which contribute to the rapid birth and diversification of lncRNA repertoires, often leading to volatile turnover across lineages.^[42] Recent chromatin conformation capture studies, including Hi-C analyses from 2023-2025, have revealed that many lncRNA loci localize at or near TAD boundaries and chromatin loops, influencing higher-order genome organization.^[40]^[43] In terms of annotation, approximately 19-20% of annotated lincRNAs overlap with or are in proximity to pseudogenes, complicating their classification and highlighting evolutionary relationships between non-coding and defunct coding elements.^[44] Tools like lncRNASNP provide resources for assessing how single nucleotide polymorphisms (SNPs) and mutations impact lncRNA secondary structures and regulatory architectures, aiding in the functional annotation of these loci.^[45]

Translation Potential

Long non-coding RNAs (lncRNAs) exhibit limited coding potential primarily due to the presence of short open reading frames (sORFs) typically shorter than 100 amino acids, which often fail to produce stable, functional proteins.^[46] Additionally, upstream ORFs (uORFs) in the 5' regions of many lncRNAs can inhibit downstream translation by stalling ribosomes or promoting premature termination.^[47] Ribosome profiling studies indicate that fewer than 5% of lncRNAs show ribosome association patterns consistent with productive translation, in contrast to protein-coding mRNAs, underscoring their predominantly non-coding nature.^[48] Despite these limitations, emerging evidence from ribosome sequencing (Ribo-seq) demonstrates that a subset of lncRNAs undergoes translation to yield micropeptides. Studies, including a 2022 analysis in Drosophila embryogenesis revealing that approximately 30% of lncRNAs harbor sORFs actively engaged by ribosomes, resulting in the regulated production of 100 to 300 micropeptides, and human studies identifying approximately 299 lncRNA-encoded small encoded peptides (SEPs) across cell lines and tissues, support this.^[49]^[50] For instance, the lncRNA ASncmtRNA, transcribed from the mitochondrial genome, encodes the micropeptide SHLP2, which localizes to mitochondria and modulates cellular processes such as energy metabolism and proliferation in tumor cells.^[51] These micropeptides often exert biologically significant roles, including regulation of cell proliferation; for example, certain lncRNA-derived peptides enhance mitochondrial complex IV activity, thereby promoting G1/S cell cycle transition.^[52] Translation of lncRNAs is further constrained by regulatory mechanisms that disfavor efficient initiation. Internal ribosome entry site (IRES) elements, which enable cap-independent translation, are rare in lncRNAs compared to viral or select cellular mRNAs.^[46] Moreover, cap-dependent scanning is often inefficient due to stable secondary structures at the 5' ends of lncRNAs, which impede ribosome progression.^[48] The translational potential of lncRNAs remains controversial, with debates centering on whether observed ribosome associations represent true protein synthesis or experimental artifacts such as non-specific binding. Recent mass spectrometry-based validations have addressed these concerns, identifying approximately 85 to 100 unique lncRNA-derived peptides in human cells, confirming their existence and tissue-specific expression.^[46] As of 2025, recent reviews highlight advances in validating lncRNA-derived micropeptides using mass spectrometry and their roles in cellular metabolism.^[53] These findings suggest that while translation is not a dominant feature of lncRNAs, the resulting micropeptides may contribute to fine-tuned regulatory functions in cellular physiology.^[54]

Regulatory Functions

Transcriptional Regulation

Long non-coding RNAs (lncRNAs) play critical roles in transcriptional regulation by modulating the initiation, pausing, and elongation phases of RNA polymerase II (Pol II)-mediated transcription through both cis- and trans-acting mechanisms. These RNAs often interact with chromatin, transcription factors, or components of the basal transcriptional machinery to fine-tune gene expression in a context-specific manner.^[3] In cis-acting mechanisms, lncRNAs primarily influence nearby genes on the same chromosome by facilitating chromatin architecture changes or recruiting regulatory complexes. For instance, enhancer-associated lncRNAs (eRNAs) can tether promoters to distal enhancers via interactions with the Mediator complex, promoting long-range DNA looping that enhances Pol II recruitment and transcriptional activation. A seminal example is the lncRNA ncRNA-a, which binds the Mediator subunit MED12 to stabilize enhancer-promoter loops, thereby activating the expression of target genes such as SNAI1 via chromatin looping.^[55] Similarly, the lncRNA FENDRR regulates mesodermal lineage genes during embryonic development by associating with Polycomb repressive complex 2 (PRC2) and Trithorax group (TrxG)/mixed-lineage leukemia (MLL) complexes, leading to balanced H3K27me3 and H3K4me3 modifications that either repress or activate transcription in a gene-specific fashion; in limb development models, FENDRR depletion disrupts these chromatin states, impairing patterning and differentiation.^[56] These cis effects ensure precise spatial control over transcription without requiring the lncRNA to diffuse far from its site of synthesis.^[57] Trans-acting mechanisms allow lncRNAs to regulate distal or multiple genes by sequestering transcription factors or modulating the core transcriptional apparatus. One prominent mode involves lncRNAs acting as decoys to inhibit transcription factor activity; for example, the lncRNA NKILA binds the NF-κB/IκB complex in the cytoplasm, masking IκB phosphorylation sites to prevent IKK-mediated IκB phosphorylation and subsequent NF-κB activation, thereby suppressing NF-κB-dependent transcriptional activation of pro-inflammatory genes.^[58] Additionally, some lncRNAs target the basal machinery, such as the C-terminal domain (CTD) of Pol II, to influence pausing and elongation; certain nuclear lncRNAs bind the unphosphorylated Pol II CTD to sterically hinder progression or recruit kinases like P-TEFb for CTD phosphorylation at Ser2, facilitating pause release.^[59] Pol III-transcribed lncRNAs, such as 7SK RNA, further exemplify this by scaffolding the 7SK small nuclear ribonucleoprotein (snRNP) complex, which sequesters P-TEFb in an inhibitory state; upon signaling, 7SK dissociates, releasing active P-TEFb to phosphorylate the Pol II CTD and promote transcriptional elongation at paused genes.^[60] Recent studies highlight lncRNAs' involvement in Pol II pausing release, a key checkpoint for productive transcription. For instance, a 2023 review of enhancer RNAs indicated that these lncRNAs coordinate with NELF and DSIF complexes at promoter-proximal regions to facilitate pause release of Pol II; their depletion stabilizes paused Pol II, impairing elongation at developmental genes; this mechanism underscores lncRNAs' role in balancing transcriptional poising for rapid responses.^[61] Overall, these regulatory strategies enable lncRNAs to integrate cellular signals into precise transcriptional outputs.

Post-Transcriptional Regulation

Long non-coding RNAs (lncRNAs) play a pivotal role in modulating mRNA splicing by interacting with spliceosome components and influencing alternative splicing patterns. A prominent example is MALAT1, which localizes to nuclear speckles and interacts with serine/arginine-rich (SR) splicing factors, thereby regulating their phosphorylation and distribution to promote efficient spliceosome assembly.00621-0) MALAT1 also stabilizes small nuclear ribonucleoproteins (snRNPs) within these subnuclear structures, facilitating the recruitment of splicing machinery to nascent pre-mRNAs.01303-2) Beyond direct interactions, lncRNAs such as NEAT1 and XIST can induce switches in alternative splicing by altering the localization of splicing factors like PTBP1, leading to exon inclusion or skipping in target transcripts.^[62] These mechanisms ensure precise post-transcriptional processing, with dysregulation often linked to cellular phenotypes like proliferation.^[63] In mRNA stability regulation, lncRNAs frequently act as competing endogenous RNAs (ceRNAs) by sequestering microRNAs (miRNAs), thereby preventing miRNA-mediated degradation of target mRNAs. The PTENP1 lncRNA exemplifies this, functioning as a ceRNA that sponges miR-21 and other miRNAs in the PTEN network, stabilizing PTEN mRNA and suppressing tumor progression in cancers like renal cell carcinoma.^[64]^[65] Similarly, lncRNAs interfere with decay pathways, such as Staufen1-mediated mRNA decay (SMD), where they form RNA duplexes with 3' untranslated regions (UTRs) of target mRNAs to recruit Staufen1 and Upf1, triggering decapping and 5'-to-3' exonucleolytic degradation.^[66] This SMD pathway, activated by lncRNAs like BACE1-AS, fine-tunes the stability of specific transcripts during stress or development. Quantitative models of ceRNA competition highlight that effective sponging requires substantial overlap in miRNA response elements (MREs), with derepression thresholds exceeding endogenous MRE abundance by at least 1.5-fold to impact miRNA repression significantly.^[67] LncRNAs also exert control over mRNA translation through mechanisms involving upstream open reading frames (uORFs) and ribosome dynamics. Some lncRNAs, such as those with translated uORFs, regulate their own expression by modulating ribosome reinitiation or stalling at uORF stop codons, indirectly influencing associated protein networks.^[68] In trans, lncRNAs like CARDINAL bind ribosomes and prevent stalling on nascent peptides during cardiac hypertrophy, thereby maintaining translational fidelity and attenuating pathological remodeling.^[69] Additionally, certain lncRNAs serve as precursors for small interfering RNAs (siRNAs) in specific contexts, such as in mammalian germ cells, where they are processed into pri-siRNAs to guide gene silencing and aid siRNA biogenesis pathways.^[2] Recent advances, including transcriptome-scale CRISPR-Cas13 screens in 2024, have identified over 700 context-specific essential lncRNAs across human cell lines, with subsets implicated in splicing networks through perturbation of alternative splicing events and spliceosome integrity.^[70] These screens revealed approximately 50 lncRNAs that, when disrupted, alter splicing factor localization and pre-mRNA processing efficiency, underscoring their non-redundant roles in post-transcriptional networks. Such findings, combined with computational models assessing MRE overlap in ceRNA interactions, provide a framework for predicting lncRNA-mediated regulatory impacts without exhaustive derivations.^[67]

Epigenetic Regulation

Long non-coding RNAs (lncRNAs) play crucial roles in epigenetic regulation by modulating chromatin states and facilitating heritable gene silencing through interactions with histone-modifying complexes. These RNAs often act in cis or trans to recruit enzymatic machinery that deposits repressive marks, such as histone H3 lysine 9 (H3K9) and lysine 27 (H3K27) trimethylation, thereby establishing and maintaining heterochromatin domains essential for developmental processes like genomic imprinting and dosage compensation. By serving as scaffolds or guides, lncRNAs enable precise targeting of these complexes to specific genomic loci, influencing gene expression without altering the underlying DNA sequence.01206-6) A prominent example of lncRNA-mediated imprinting control is the Airn lncRNA, which silences the imprinted Igf2r gene in cis during mouse embryonic development. Airn recruits the histone methyltransferase G9a to the Igf2r promoter, leading to H3K9 dimethylation and subsequent transcriptional repression in extraembryonic tissues. This mechanism ensures parent-of-origin-specific gene expression, with Airn transcription initiating as early as the blastocyst stage and persisting to maintain silencing. Disruption of Airn or G9a abolishes this repression, highlighting the lncRNA's direct role in epigenetic imprinting.00205-5) In X-chromosome inactivation (XCI), the Xist lncRNA coats the future inactive X chromosome (Xi) in female mammals, recruiting Polycomb repressive complex 2 (PRC2) to catalyze H3K27me3 deposition across large chromatin domains. This coating spreads bidirectionally from the Xist locus, initiating chromosome-wide silencing and forming the Barr body. The antisense Tsix lncRNA antagonizes Xist by competing for shared regulatory elements and preventing Xist upregulation on the active X chromosome, thus ensuring monoallelic Xist expression and proper XCI choice. PRC2 recruitment by Xist involves specific RNA domains, such as the A-repeat, which directly bind EZH2, the catalytic subunit of PRC2, to propagate repressive marks.01415-3)81659-2)00093-5) Beyond imprinting and XCI, lncRNAs like HOTAIR mediate epigenetic modifications at HOX gene loci by bridging PRC2 and lysine-specific demethylase 1 (LSD1). HOTAIR tethers PRC2 to induce H3K27me3 and LSD1 to remove the active H3K4me mark, coordinately repressing HOX genes in trans across chromosomes. This dual action establishes bivalent chromatin states that poise developmental genes for activation or silencing. Similarly, telomeric repeat-containing RNA (TERRA) promotes heterochromatin formation at chromosome ends by recruiting PRC1 and PRC2, facilitating H3K9me3, H3K27me3, and H4K20me3 marks that protect telomeres from DNA damage and recombination. TERRA's localization to telomeric repeats stabilizes these repressive domains, preventing telomere dysfunction.00501-9)^[71] Recent studies have revealed advanced mechanisms, including lncRNAs' involvement in phase-separated condensates that sustain epigenetic memory. For instance, certain lncRNAs nucleate liquid-liquid phase separation of PRC2 and other factors, concentrating them at target loci to reinforce H3K27me3 propagation during cell division. Additionally, epitranscriptomic modifications like N6-methyladenosine (m6A) on lncRNAs influence PRC2 binding; m6A-marked chromatin-associated lncRNAs recruit PRC2 via readers like RBFOX2, enhancing focal H3K27me3 deposition and gene silencing in hematopoiesis. In breast cancer, m6A on HOTAIR modulates its stability and interaction with epigenetic complexes, underscoring the interplay between RNA modifications and chromatin regulation.01206-6)^[72]^[73]

Genome Maintenance

Long non-coding RNAs (lncRNAs) play critical roles in regulating DNA replication timing by influencing chromatin states at replication origins. For instance, ASAR lncRNAs, such as ASAR6 and ASAR15, control chromosome-wide replication timing in cis by promoting the spreading of heterochromatin, which delays replication initiation in specific genomic regions.^[74] These lncRNAs interact with chromatin-modifying complexes during the cell cycle, ensuring coordinated replication with phases like S phase progression and preventing untimely origin firing that could lead to genomic instability.^[75] In maintaining chromosome stability, lncRNAs contribute to telomere protection and centromere function. The telomeric repeat-containing RNA (TERRA), a lncRNA transcribed from subtelomeric regions, regulates telomere length by inhibiting telomerase activity through direct binding to the enzyme's RNA component, thus preventing excessive elongation.^[76] Additionally, TERRA promotes homologous recombination at telomeres by forming R-loops that facilitate DNA repair pathways, supporting alternative lengthening of telomeres (ALT) in telomerase-deficient cells.^[77] At centromeres, lncRNAs like CCTT mediate kinetochore assembly by facilitating RNA-DNA and RNA-protein interactions that recruit the centromere protein CENP-C to centromeric DNA, ensuring proper spindle attachment during mitosis.^[78] LncRNAs are integral to the DNA damage response (DDR) by recruiting repair factors and modulating damage signaling. The lncRNA NORAD maintains genomic stability by sequestering PUMILIO proteins, which otherwise destabilize mRNAs involved in cell cycle control and DNA repair; NORAD depletion leads to increased DNA damage and aneuploidy.^[79] In R-loop resolution, recent studies highlight lncRNAs' roles in preventing persistent RNA-DNA hybrids that trigger DNA breaks; for example, TERRA-associated R-loops at telomeres are resolved to support recombination-based repair, with dysregulation linked to ALT activation in cancer cells. Alu-derived lncRNAs, such as those in lincRNA-p21, aid in DDR by forming double-stranded RNA structures via inverted Alu repeats, which activate protein kinase R (PKR) to enhance p53-mediated repair pathways following double-strand breaks.^[80] Quantitative impacts of lncRNAs on replication dynamics underscore their protective functions. Depletion of the chromatin-associated lncREST results in sustained replication fork progression, increasing fork speed by approximately 20-30% under stress conditions and leading to unrepaired DNA damage due to bypassed stalling signals.^[81] Similarly, knockdown of the ATR/Chk1-interacting lncRNA (ACIL) suppresses replication fork speed by up to 40% during hydroxyurea-induced stress, highlighting lncRNAs' role in stabilizing fork velocity for error-free duplication.^[82]

Evolutionary Aspects

Sequence Conservation

Long non-coding RNAs (lncRNAs) generally exhibit low sequence conservation at the nucleotide level compared to protein-coding mRNAs, with most showing less than 10% sequence identity beyond mammalian species due to rapid evolutionary turnover and relaxed selective constraints.^[83] In comparisons between human and mouse, exonic sequences of lncRNAs typically display low identity, often below 30%, such as 22% in cases like the Rmst lncRNA, reflecting weaker purifying selection on primary sequences.^[84] This limited conservation is evident in large-scale genomic alignments, where only a small fraction of lncRNAs—estimated at around 5%—maintain sequence similarity across broader vertebrate clades.^[85] Promoters of lncRNAs demonstrate higher conservation than their exonic regions, with PhastCons conservation scores around 0.2-0.3 in human-mouse comparisons, comparable to those of protein-coding genes, suggesting stronger selective pressure on transcriptional initiation sites.^[83] Functional domains within lncRNAs, such as RNA-binding motifs or repeat elements, often show elevated conservation; for instance, the GAS5 lncRNA retains approximately 70% nucleotide homology in its exons between human and mouse.^[86] Additionally, syntenic preservation occurs at lncRNA loci across mammals, with approximately 25% of human lncRNAs having orthologs in mice based on genomic synteny and expression patterns, indicating that genomic context contributes to evolutionary stability even when sequences diverge.^[87] Comparative genomics tools reveal that lncRNAs have lower PhastCons scores than mRNAs, with mean placental mammal scores for lncRNA exons typically below those of coding exons, underscoring reduced nucleotide-level preservation.^[83] Alignments via the UCSC Genome Browser facilitate these analyses by mapping multi-species sequences and identifying conserved patches.^[86] A 2023 pan-eukaryote study highlighted evolutionary bursts of lncRNA conservation particularly in vertebrates, where multidimensional analyses (including PhastCons thresholds >0.58) identified subsets with enhanced sequence retention linked to regulatory roles.^[88] Notable exceptions include ultra-conserved elements (UCEs) within lncRNAs, such as transcribed ultra-conserved RNAs (T-ucRNAs or ucRNAs), which exhibit 100% identity over >200 nucleotides across human, mouse, and rat genomes, comprising 481 such regions with high functional potential.^[89] As of 2024, computational tools have identified additional conserved lncRNA functions across vertebrates using multi-omics data.^[90]

Functional Conservation

Functional conservation of long non-coding RNAs (lncRNAs) refers to the preservation of their biological roles across species despite limited sequence similarity, often through maintained interactions with conserved cellular machinery or regulatory networks. A key example of functional synteny is observed in X-chromosome dosage compensation, where the lncRNA Xist in placental mammals orchestrates X-inactivation, while a functional ortholog, Rsx (RNA-on-the-silent X), performs a similar cis-acting role in marsupials by silencing the paternal X chromosome during imprinted X-chromosome inactivation. This conservation highlights how lncRNA-mediated mechanisms can evolve to achieve equivalent dosage balance in diverse mammalian lineages. Similarly, approximately 25% of annotated human lncRNAs exhibit functional orthologs in mice, as evidenced by shared expression patterns, genomic synteny, and phenotypic effects upon perturbation, underscoring the selective pressure on lncRNA loci for retained regulatory functions despite sequence divergence.^[91]^[86] Adaptive evolution of lncRNAs is particularly evident in primates, where rapid turnover of brain-specific lncRNAs has contributed to lineage-specific neurodevelopmental traits. For instance, many primate lncRNAs display transient expression during early brain development, with structural conservation but high sequence variability, suggesting that their roles in modulating neuronal differentiation and synaptic plasticity are preserved through secondary structures or binding motifs rather than primary sequences. This turnover is exemplified by de novo lncRNA-derived genes unique to humans that encode proteins influencing brain-specific functions, indicating accelerated evolution in cognitive-related pathways. Furthermore, lncRNA interactions with conserved RNA-binding proteins (RBPs), such as TLS/FUS, demonstrate functional preservation; the Drosophila lncRNA hsrω, which regulates FUS arginine dimethylation, rescues ALS-like phenotypes in human cellular models, illustrating cross-species conservation of RBP-lncRNA complexes in stress granule formation and neurodegeneration.^[92]^[93]^[94] Cross-species evidence further supports lncRNA functional conservation through comparable knockout phenotypes. The lncRNA NEAT1, essential for paraspeckle assembly in mammals, is conserved in marsupials where it supports paraspeckle formation during late gestation, indicating preserved architectural roles in nuclear organization across mammals. In evolutionary developmental (evo-devo) contexts, recent studies reveal lncRNAs in plants that mirror animal immunity by fine-tuning stress responses; for example, conserved lncRNA motifs in Arabidopsis regulate pathogen defense and abiotic stress tolerance via epigenetic silencing, paralleling immune modulation in animals through shared mechanisms like chromatin remodeling. These findings highlight lncRNAs' adaptability in stress adaptation across kingdoms.^[95]^[96] Metrics of functional conservation often surpass sequence-level analyses, as demonstrated by phenotypic rescue experiments and network-level preservation. In cross-species assays, human lncRNA orthologs rescue knockout phenotypes in zebrafish models, such as restoring cellular proliferation defects, confirming functional equivalence despite sequence divergence. Network-level conservation is notably higher, with ceRNA (competing endogenous RNA) hubs—where lncRNAs act as miRNA sponges—preserved across tumors and species, as hub lncRNAs dominate regulatory interactions in cancer hallmarks, indicating robust evolutionary retention of interaction networks over individual sequences. These approaches reveal that lncRNA functions are under stronger selective constraint at the systems level, facilitating orthologous roles in development and disease.^[90]^[97]

Biological and Pathological Roles

Roles in Development and Physiology

Long non-coding RNAs (lncRNAs) play pivotal roles in developmental processes by facilitating essential mechanisms such as X-chromosome dosage compensation and genomic imprinting. The lncRNA Xist is crucial for X-chromosome inactivation in female mammals, where it coats the inactive X chromosome to silence gene expression and equalize dosage between sexes.^[98] Similarly, Kcnq1ot1, a paternally expressed lncRNA within the Kcnq1 imprinting domain on chromosome 11p15.5, mediates epigenetic silencing of neighboring genes, ensuring proper fetal growth and development through monoallelic expression.^[99] In limb development, lncRNAs contribute to patterning by regulating key signaling pathways; for instance, the lncRNA Maenli acts as a limb-specific regulator of the transcription factor En1, which in turn influences Fgf8 expression to guide anterior-posterior limb patterning.^[100] In physiological contexts, lncRNAs modulate immune responses and stress adaptation to maintain organismal homeostasis. NEAT1 lncRNA organizes nuclear paraspeckles that sequester antiviral factors, enhancing the host's defense against viral infections such as hantavirus by promoting interferon-stimulated gene expression.^[101] Recent studies have also implicated NEAT1 in natural killer (NK) cell function, where it can inhibit cytotoxicity in pathological contexts like sepsis by acting as a competing endogenous RNA (ceRNA) for miR-125 to upregulate MCEMP1, as highlighted in 2025 reviews on lncRNA roles in NK biology.^[102] In plants, lncRNAs aid stress adaptation and growth under abiotic challenges; for example, various lncRNAs regulate hormone signaling and nutrient uptake to enhance tolerance to drought and salinity, as summarized in 2023-2024 reviews.^[103] LncRNAs further contribute to tissue homeostasis through metabolic and rhythmic regulation. The imprinted lncRNA H19 promotes skeletal muscle insulin sensitivity and glucose uptake by activating the AMPK pathway, thereby fine-tuning systemic glucose homeostasis.^[104] In circadian physiology, lncRNAs influence chromatin dynamics to sustain rhythmic gene expression. 2024 findings reveal oscillations in chromatin accessibility at core clock gene loci, establishing "chromatin clocks" for temporal homeostasis.^[105] These functions often integrate within multi-lncRNA networks during organogenesis. In cardiac development, the lncRNA Braveheart coordinates a network of cardiovascular genes by associating with chromatin complexes, promoting the transition from multipotent mesoderm to committed cardiac progenitors.^[106] Such networks underscore the broader physiological orchestration by lncRNAs, linking regulatory mechanisms to developmental and homeostatic outcomes.

Associations with Diseases

Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of various human diseases through their dysregulation, which disrupts normal regulatory functions and contributes to disease progression. In cancer, lncRNAs can act as oncogenes or tumor suppressors, influencing tumor growth, metastasis, and therapy resistance. For instance, the lncRNA HOTAIR is upregulated in primary breast tumors and promotes metastasis by reprogramming chromatin through interactions with the Polycomb Repressive Complex 2 (PRC2), leading to epigenetic silencing of tumor suppressor genes. HOTAIR expression correlates with poorer metastatic-free and overall survival in breast cancer patients. Similarly, HOTAIR drives breast cancer progression by modulating multiple signaling pathways, including those involved in cell migration and invasion. Recent reviews highlight the role of lncRNAs like HOTAIR in shaping the tumor microenvironment, where they facilitate immune evasion and stromal interactions to support metastasis. In contrast, the lncRNA GAS5 functions as a tumor suppressor by inhibiting cell proliferation, migration, and invasion while promoting apoptosis across multiple cancers, including breast, gastric, and lung carcinomas; its downregulation is associated with advanced disease stages and reduced patient survival. In cardiovascular diseases, lncRNAs contribute to vascular dysfunction and cardiac remodeling. The lncRNA ANRIL, located at the 9p21 locus, promotes atherosclerosis by acting as a scaffold for PRC1 and PRC2 complexes, repressing genes involved in inflammation and lipid metabolism, which leads to plaque formation and instability. Genetic variants in the ANRIL locus are strongly associated with atherosclerosis risk. In heart failure, the lncRNA MIAT is upregulated and regulates myocardial hypertrophy and fibrosis, making it a promising therapeutic target; recent studies from 2025 emphasize MIAT's role in pathological cardiac remodeling post-myocardial infarction and its potential for siRNA-based interventions to improve cell viability. Neurological and immune-related diseases also feature lncRNA dysregulation with causal implications. In Alzheimer's disease, the lncRNA BACE1-AS stabilizes BACE1 mRNA by forming RNA duplexes that prevent its degradation, thereby increasing β-secretase activity and amyloid-β production, which exacerbates neuronal damage. Elevated BACE1-AS levels have been observed in Alzheimer's patients and amyloid precursor protein transgenic models. For immune disorders, lncRNAs modulate natural killer (NK) cell function and contribute to diseases like cancers and autoimmune conditions; a 2025 review details how lncRNAs such as MALAT1 and RMRP regulate NK cell activation, cytotoxicity, and immune escape in tumor microenvironments, with dysregulation linked to impaired immunomodulation in NK cell-associated pathologies. LncRNAs serve as valuable biomarkers due to their stability and disease-specific expression patterns. Circulating lncRNAs, detectable in blood or urine, offer non-invasive diagnostic potential; for example, PCA3 is highly specific to prostate cancer and is FDA-approved for detecting high-grade tumors via urine assays, where its overexpression correlates with disease progression and androgen receptor signaling. Genome-wide association studies (GWAS) have identified disease-associated variants in lncRNA loci, with recent analyses indicating that a substantial proportion—estimated up to around 30%—of such variants fall within lncRNA regions due to expanded annotations, influencing susceptibility to cancers, cardiovascular diseases, and immune disorders through altered expression or structure.^[107]

Therapeutic Potential

Targeting Approaches

Antisense oligonucleotides (ASOs) represent a primary strategy for targeting long non-coding RNAs (lncRNAs) by inducing their degradation through recruitment of RNase H enzymes. Gapmer ASOs, which feature a central DNA segment flanked by modified nucleotides, hybridize to target lncRNA sequences and trigger cleavage by endogenous RNase H, effectively reducing lncRNA levels. For instance, LNA-gapmer ASOs targeting the oncogenic lncRNA MALAT1 have demonstrated inhibition of gene expression in proteasome subunits, leading to anti-proliferative effects in multiple myeloma models and advancing to preclinical evaluations for broader cancer applications.^[108] Locked nucleic acids (LNAs), incorporated into ASOs, enhance binding affinity and nuclease resistance, thereby improving stability and potency in vivo; LNA-modified gapmers have shown superior downregulation of nuclear lncRNAs compared to unmodified counterparts, with applications in silencing disease-associated lncRNAs like Xist.^[109]^[110] RNA interference (RNAi) approaches utilize small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) to achieve sequence-specific degradation of lncRNA transcripts via the RNA-induced silencing complex (RISC). These tools have been widely applied to knock down lncRNAs in cellular studies, revealing functional roles in gene regulation; for example, siRNAs targeting nuclear lncRNAs like NEAT1 effectively suppress paraspeckle formation and associated pathological processes.^[111] Recent advances in CRISPR-Cas13 systems further refine RNAi-like targeting by enabling precise RNA editing and cleavage with high specificity, avoiding off-target DNA effects; 2024 developments in Cas13-based screens have identified essential lncRNAs through transcriptome-wide perturbations, demonstrating strand- and transcript-specific silencing in cancer cells.^[112]^[113] Small molecules offer an alternative for modulating lncRNA function by binding to specific structural motifs, such as triple helices or G-quadruplexes, thereby disrupting protein interactions or stability. Compounds targeting the triple helix in lncRNAs like MALAT1 have been shown to reduce RNA levels and inhibit downstream oncogenic signaling, providing a scaffold for structure-based drug design. For NEAT1, small molecules that bind G-quadruplex motifs interfere with NONO protein recruitment, destabilizing paraspeckle assembly and attenuating immune responses in disease models. A 2025 review has discussed the potential of small-molecule inhibitors targeting lncRNAs like CHRF to block fibrotic pathways by preventing lncRNA-mediated epigenetic changes in cardiac tissue.^[114]^[115]^[116] Gene therapy strategies employ viral vectors, such as adeno-associated virus (AAV), to deliver suppressors that overexpress RNAi components or decoy elements targeting lncRNAs. These approaches can be combined with miRNA mimics to enhance efficacy.

Challenges and Recent Advances

One major challenge in developing therapeutics targeting long non-coding RNAs (lncRNAs) is efficient delivery, particularly due to their frequent nuclear localization, which complicates access for cytoplasmic-acting agents like small interfering RNAs (siRNAs). Antisense oligonucleotides (ASOs) have shown greater efficacy in silencing nuclear lncRNAs compared to RNA interference approaches, which perform better on cytoplasmic ones, highlighting the need for localization-specific strategies. Off-target effects further hinder progress, as non-specific binding can lead to unintended gene regulation and toxicity. To address these, lipid nanoparticles (LNPs) have emerged as a promising delivery platform, with formulations like those incorporating ionizable lipids enabling liver-specific uptake via apolipoprotein E-mediated endocytosis, as demonstrated in mRNA therapeutics and adaptable to lncRNA modulators. Specificity remains a critical barrier, as lncRNAs often adopt complex secondary structures that impede binding of therapeutic agents, while isoform variability across tissues can result in incomplete or heterogeneous targeting. Additionally, synthetic RNA analogs risk activating innate immune responses through Toll-like receptors, leading to cytokine release and potential toxicity, which necessitates chemical modifications such as 2'-O-methylation to enhance stability and reduce immunogenicity. These issues underscore the importance of high-fidelity design tools to minimize off-target interactions and isoform-specific effects. Clinical translation remains primarily preclinical, with studies such as a 2024 investigation demonstrating that LNP-delivered ASOs targeting HOTAIR reduced tumorigenic properties in solid tumor models, suggesting potential for future evaluations in advanced cancers.^[117] In cardiovascular applications, 2025 preclinical successes include lncRNA MIR181A1HG silencing, which significantly attenuated atherosclerotic lesion burden in aortic models by modulating vascular inflammation, offering promise for plaque stabilization therapies. Emerging technologies are accelerating lncRNA therapeutic development, including AI-driven models like graph neural networks that predict lncRNA-disease associations with high accuracy; for example, the 2025 LDA-GMCB framework integrates multi-head self-attention for scalable inference of novel links. Base editing strategies, particularly RNA-specific deaminases fused to guide RNAs, enable precise correction of lncRNA variants influencing stability and function, as evidenced by tools predicting editing impacts in databases like LNCediting. Insights from plant-derived lncRNAs are informing agrobiotech, where 2025 reviews highlight their roles in stress tolerance and development, inspiring engineered crops with enhanced resilience through lncRNA modulation.

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Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity.
[100]
Therapeutic Targeting of Long Non-Coding RNAs in Cancer - NIH
One of the major advances in ASO chemistry is the development of locked nucleic acids (LNA) and S-constrained ethyl (cEt) modifications, which have ...
[101]
Locked nucleic acids (LNAs) reveal sequence requirements ... - PNAS
We target LNAs at Xist RNA and show displacement from the X chromosome with fast kinetics. Xist transcript stability is not affected.
[102]
Long Non-Coding RNA Targeting and Transcriptional De-Repression
RNAi is best known for the work demonstrating that ∼22 nucleotide small interfering RNA (siRNAs) or microRNAs (miRNAs) could be used to functionally target and ...
[103]
Discovering the crucial function of long noncoding RNAs - Nature
Dec 11, 2024 · They use the RNA-targeting Cas13 nuclease to develop a transcriptome-wide CRISPR perturbation screen that targets lncRNA, and identify 778 ...
[104]
Article Transcriptome-scale RNA-targeting CRISPR screens reveal ...
Dec 26, 2024 · We have developed RNA-targeting CRISPR screens to systematically perturb lncRNAs on a transcriptome scale with transcript- and strand-specificity.
[105]
Selective Small-Molecule Targeting of a Triple Helix Encoded ... - NIH
First, the RNA structure itself can be disrupted (e.g., compound 16) to reduce MALAT1 levels. Second, small-molecule binding may serve to inhibit other ...
[106]
G-quadruplexes offer a conserved structural motif for NONO ...
Jun 4, 2020 · The long non-coding RNA NEAT1 serves as a scaffold for the assembly of paraspeckles, membraneless nuclear organelles involved in gene regulation ...
[107]
LncRNA CHRF: molecular mechanisms and therapeutic potentials ...
Jun 19, 2025 · This mechanistic insight establishes a solid foundation for designing CHRF-directed small-molecule inhibitors. 5 Conclusion and discussion.2.1 Lncrna Chrf In... · 2.2 Lncrna Chrf In Cancers · 2.3 Lncrna Chrf In Fibrotic...
[108]
Long Non-coding RNA Based Therapy for Cardiovascular Disease
Sep 3, 2025 · One of the most relevant and widely studied lncRNAs in CVDs is MIAT, an intergenic lncRNA located on chromosome 22. It has been reported that ...
[109]
Therapeutic potential of synthetic microRNA mimics based on the ...
Mar 22, 2025 · These results suggest that mimics based on the consensus sequence of the miR-15/107 group have therapeutic potential in a range of cancer types.
[110]
A combinatorial microRNA therapeutics approach to suppressing ...
MicroRNA mimics are excellent therapeutic candidates because of their ability to repress multiple oncogenic pathways at once. Here we treated the aggressive ...