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Circular RNA

Circular RNAs (circRNAs) are a class of endogenous, single-stranded RNA molecules that form a covalently closed, continuous loop structure without free 5′ or 3′ ends, generated primarily through back-splicing of precursor mRNA (pre-mRNA) exons.^[1] This unique topology confers exceptional stability, with half-lives of 19–24 hours compared to 4–7 hours for linear mRNAs, rendering them resistant to exonuclease degradation.^[1] CircRNAs are ubiquitously expressed across species, from viruses to mammals, and represent a substantial portion of the transcriptome, with over 100,000 distinct circRNAs identified in human brain neurons alone.^[2] The biogenesis of circRNAs involves canonical splicing machinery but proceeds in a reverse direction, where a downstream splice donor joins an upstream splice acceptor, often facilitated by complementary intronic sequences or RNA-binding proteins such as Quaking (QKI) or Muscleblind (MBL).^[3] They are classified into major types, including exonic circRNAs (ecircRNAs), which consist primarily of spliced exons; exonic-intronic circRNAs (EIciRNAs), retaining introns; circular intronic RNAs (ciRNAs), derived from lariat introns; and tRNA intronic circRNAs (tricRNAs) from pre-tRNA splicing.^[1] Post-transcriptional modifications, such as N6-methyladenosine (m6A), further regulate their export, localization, and degradation via pathways involving YTH domain-containing proteins and RNases.^[3] Functionally, circRNAs exert diverse regulatory roles, including acting as microRNA (miRNA) sponges to sequester and inhibit miRNA activity—exemplified by CDR1as, which harbors over 70 binding sites for miR-7—thereby modulating gene expression.^[1] They also interact with proteins to form complexes that influence transcription, such as circPAIP2 enhancing transcription of its parental gene, or translation, where select circRNAs like circFBXW7 encode functional peptides via internal ribosome entry sites (IRES) or m6A-driven mechanisms.^[3] In the mammalian brain, circRNAs are highly enriched in neuronal synapses and dynamically upregulated during differentiation, suggesting roles in neural development and plasticity.^[4] Dysregulation of circRNAs is implicated in numerous diseases, particularly cancers, where they promote tumorigenesis through miRNA sponging or protein modulation—such as circFoxo3 enhancing anti-apoptotic effects via p53-MDM2 interactions—and cardiovascular or neurological disorders.^[3] Their tissue-specific expression, stability, and detectability in biofluids position circRNAs as promising biomarkers and therapeutic targets, with ongoing research exploring their translational potential in precision medicine.^[1]

Discovery and Historical Context

Early Observations of Circular RNAs

The first reports of circular RNAs emerged in 1976, when H. L. Sanger and colleagues identified viroid-like, single-stranded covalently closed circular RNA molecules in infected plant cells, which they characterized as highly base-paired rod-like structures using electron microscopy and enzymatic assays.^[5] These findings were initially met with skepticism, as the circular forms were dismissed by some as experimental artifacts or contaminants rather than biologically relevant entities in eukaryotic cells. In 1979, M. T. Hsu and M. Coca-Prados provided direct visual evidence of circular RNAs in the cytoplasm of eukaryotic cells, including HeLa cells, through electron microscopy, revealing lariat-like structures indicative of RNA circularization and describing them as containing "scrambled exons" resulting from non-canonical splicing.^[6] This observation extended the presence of circular RNAs beyond viral contexts to host cellular environments, though they were still viewed as rare anomalies possibly arising from splicing errors in plant mitochondria and other systems.^[7] A significant advancement came in 1991, when J. M. Nigro and colleagues reported exon scrambling in transcripts from the DCC tumor suppressor gene in human colorectal tumors, identifying abnormally spliced RNAs where exons were joined in non-collinear order, suggesting a mechanism of back-splicing that produces circular forms.^[8] These discoveries highlighted circular RNAs as potential products of alternative splicing in mammalian cells, yet they remained underappreciated due to prevailing biases toward linear RNA detection.^[9] Early challenges in recognizing circular RNAs stemmed from detection methods optimized for linear transcripts, such as poly-A selection, which systematically underrepresented non-polyadenylated circular species, leading to their perception as infrequent splicing byproducts rather than distinct RNA entities.^[7] Key experiments confirming their circular nature included electron microscopy for visualizing closed-loop structures, as demonstrated in the 1979 study, and later RNase R exonuclease resistance assays, which selectively degrade linear RNAs while leaving circular forms intact, thereby verifying covalent closure.^[6]^[10]

Genome-Wide Identification and Abundance Revelation

The advent of high-throughput RNA sequencing (RNA-seq) technologies in the early 2010s revolutionized the detection of circular RNAs (circRNAs), shifting from sporadic observations to genome-wide identification and revealing their unexpected abundance across species. In 2012, Salzman et al. employed deep RNA-seq on total RNA with ribosomal RNA (rRNA) depletion from diverse human cell lines, including normal fibroblasts and leukemia cells, identifying circular isoforms from hundreds of genes where these circRNAs often predominated over linear counterparts in some genes, estimated at about 10% of transcripts from 1–2% of expressed genes.^[11] Their analysis underscored a previously underappreciated splicing outcome in human gene expression.^[11] Building on this, 2013 marked pivotal advancements with independent studies that cataloged thousands of circRNAs using specialized computational tools. Memczak et al. analyzed rRNA-depleted RNA-seq data from human, mouse, and nematode samples, developing a pipeline to detect back-splice junctions and identifying over 2,700 conserved circRNAs in humans, many exhibiting tissue-specific expression.^[12] Concurrently, Jeck et al. introduced the find_circ algorithm, which filters for paired-end reads mapping to back-splice sites, applied to RNase R-enriched RNA-seq from human fibroblasts and mouse tissues, revealing approximately 27,000 circRNA candidates that were abundant, evolutionarily conserved, and frequently associated with Alu repeats in flanking introns. These tools enabled systematic annotation, demonstrating circRNAs as a pervasive feature of eukaryotic transcriptomes rather than rare anomalies. By 2014, analyses of large-scale datasets further illuminated circRNA distribution, with the ENCODE project's rRNA-depleted (Ribozero) RNA-seq from multiple human tissues highlighting their enrichment in neural samples compared to other organs.^[13] This was corroborated in 2015 by deep sequencing of mouse brain tissues, which showed circRNAs comprising up to 10-20% of back-spliced reads in neuronal contexts, far exceeding levels in non-neural tissues.^[4] Tissue-specific patterns emerged prominently in neural systems, where circRNAs were upregulated during development and synaptic activity; for instance, the circRNA CDR1as (also known as ciRS-7), derived from the CDR1 locus, exhibited exceptionally high expression in the cerebellum, particularly in granule cells, acting as a potent microRNA sponge.^[4]^[14] Advancements from 2015 to 2018 refined detection precision and explored pathological contexts. The upgraded CIRCexplorer2 pipeline, introduced in 2016, improved back-splice junction identification by integrating TopHat-Fusion for chimeric read alignment and enabling comprehensive annotation of alternative back-splicing events across diverse RNA-seq datasets. During this period, studies in Alzheimer's disease models revealed dysregulated circRNA profiles; for example, hippocampal RNA-seq from 5xFAD transgenic mice identified 143 differentially expressed circRNAs, including those modulating amyloid-beta pathways, suggesting roles in neurodegeneration.^[15] Overall quantification across these efforts indicated that circRNAs can represent up to 20% of detected transcripts in specific conditions like brain tissue, with their closed-loop structure conferring greater stability—often with half-lives exceeding 24 hours—compared to linear mRNAs, which degrade within hours.^[4] This stability, validated through actinomycin D chase assays, positions circRNAs as durable regulatory elements in cellular homeostasis. Subsequent tools like CIRI2 (2015) and updates through the 2020s have further improved detection accuracy across species and conditions.^[16]

Biogenesis Mechanisms

Back-Splicing and Splicing Variants

Back-splicing represents the core mechanism of circular RNA (circRNA) biogenesis, in which a downstream 5′ splice donor site is covalently ligated to an upstream 3′ splice acceptor site on the pre-mRNA transcript, generating a continuous loop without free ends, 5′ caps, or poly(A) tails.^[17] This process contrasts with canonical splicing, where exons are joined in sequential 5′ to 3′ order to form linear mRNAs; back-splicing instead proceeds in reverse orientation using the same spliceosomal machinery, often yielding both a circRNA and a linear byproduct with skipped exons.^[18] Although initially viewed as aberrant splicing errors, back-splicing is now recognized as a regulated, non-canonical pathway that produces diverse RNA circles across eukaryotes. The biogenesis of circRNAs via back-splicing involves several key steps, starting with the spatial proximity of splice sites achieved through pre-mRNA secondary structure formation, such as base-pairing between reverse complementary motifs in flanking introns.^[17] This brings the donor and acceptor into close contact, enabling spliceosome assembly and formation of a lariat intermediate, akin to canonical intron excision but resolved to circularize the exons or introns.^[18] In the exon-skipping model, alternative splicing first generates a lariat containing the prospective circRNA sequence, followed by heads-to-tails ligation; alternatively, direct back-splicing can occur without prior skipping.^[19] Such events can produce scrambled exon arrangements, where non-sequential exons are joined, reflecting variations in splicing patterns rather than random errors. Back-splicing yields multiple circRNA variants based on genomic origin and composition. Exonic circRNAs (ecircRNAs), the most prevalent type accounting for 80–90% of detected circRNAs, are predominantly composed of one or more spliced exons lacking intronic sequences. Intronic circRNAs (ciRNAs) arise from back-spliced introns that resist debranching and degradation, while exonic-intronic hybrids (EIciRNAs) retain both exons and introns in the circle. Intergenic circRNAs form from sequences between genes, and full-intron circRNAs represent cases where entire introns are looped without exonic inclusion.^[18] Early experimental validation of back-splicing relied on two-dimensional gel electrophoresis, which resolved circular RNAs as distinct spots with altered electrophoretic mobility compared to linear isoforms, confirming their topological closure and distinguishing them from linear contaminants. Complementary elements like Alu repeats can briefly enhance splice site juxtaposition during this process.

Regulatory Factors in CircRNA Formation

The formation of circular RNAs (circRNAs) through back-splicing is tightly regulated by cis-acting sequence elements that promote pre-mRNA looping. Complementary repeats, such as Alu elements within flanking introns, facilitate base-pairing across introns, thereby stabilizing the looped structure necessary for the spliceosome to join upstream exons to downstream ones.^[17] In primates, reverse complementary Alu sequences (rcAlu) are particularly enriched in circRNA-generating loci, driving higher circularization efficiency compared to linear splicing; for instance, in humans, approximately 88% of circRNAs are flanked by such intronic Alu elements.^[17]^[20] These elements create a competitive dynamic where intra-intronic pairing favors linear RNA production, while inter-intronic pairing slows linear splicing progression and boosts circRNA yield by up to several-fold in reporter assays. Trans-acting splicing factors further modulate circRNA biogenesis by binding these intronic repeats to enhance loop stability. The RNA-binding protein Quaking (QKI) recognizes QKI-binding motifs in introns and dimerizes to bridge flanking regions, promoting back-splicing and increasing circRNA levels during processes like epithelial-mesenchymal transition; depletion of QKI reduces circRNA output from multiple loci by over 50%.^[21] Similarly, Muscleblind (MBL/MBNL1) binds intronic repeats adjacent to circRNA exons, stabilizing loops and inhibiting canonical splicing, as seen in its autoregulation where MBL overexpression elevates its own circMBL isoform.^[22] These factors collectively shift the splicing equilibrium toward circularization without altering the core spliceosomal machinery. RNA editing by adenosine deaminases acting on RNA (ADAR) enzymes introduces A-to-I modifications that disrupt or, in some cases, fine-tune base-pairing for circularization. ADAR1 primarily suppresses circRNA formation by editing dsRNA structures formed by Alu repeats, destabilizing loops and reducing back-splicing efficiency; ADAR1 knockdown significantly elevates circRNA abundance genome-wide, with many showing >2-fold increases.^[23] However, site-specific editing can enhance circularization if it strengthens complementary pairing elsewhere, as exemplified in circNFIX where ADAR-mediated edits in flanking introns modulate loop formation and circRNA expression in neural contexts. Epigenetic modifications influence circRNA biogenesis by altering chromatin accessibility at splice sites. Histone marks such as H3K36me3 and H3K79me2 negatively correlate with circRNA production across cell types, likely by recruiting factors that favor linear splicing over back-splicing through enhanced exon definition.^[24] DNA methylation at promoter CpG islands represses host gene transcription, indirectly limiting pre-mRNA availability for circularization, while hypomethylation promotes open chromatin conducive to alternative splicing events yielding circRNAs.^[25] More recently, additional RNA-binding proteins such as FUS and NOVA2 have been shown to promote back-splicing, while the DExH-box helicase DHX9 suppresses it by unwinding intron base-pairing.^[1] These layers integrate with sequence and protein regulators to fine-tune circRNA output in a context-dependent manner.

Structural Characteristics

Classification by Origin and Type

Circular RNAs (circRNAs) are classified primarily by their genomic origin, which determines their composition and potential regulatory roles. Exonic circRNAs (ecircRNAs) are derived exclusively from one or more exons of protein-coding genes and represent the most abundant class, comprising over 80% of detected circRNAs in eukaryotic transcriptomes.^[26] Intronic circRNAs (ciRNAs) originate from introns that evade typical splicing and degradation pathways, while exonic-intronic circRNAs (EIciRNAs) incorporate both exons and retained introns, often preserving regulatory elements like intronic repeats.^[27] Intergenic circRNAs arise from non-coding intergenic regions or read-through transcripts spanning adjacent genes, forming a less common but diverse category.^[27] Another class, tRNA intronic circRNAs (tricRNAs), are generated from the introns of precursor tRNAs (pre-tRNAs) during tRNA splicing.^[1] Structurally, circRNAs vary in their exon composition and processing state. Single-exon circRNAs consist of a solitary exon looped via back-splicing, often from unusually long exons, whereas multi-exon circRNAs, which are more prevalent, include two or more exons joined covalently, typically ranging from 2 to 15 exons per circle.^[28] Lariat circRNAs retain the branched 2',5'-phosphodiester bond from splicing intermediates, distinguishing them from fully processed circRNAs, which form linear-like circles after debranching and exhibit higher stability.^[29] For instance, ciRNAs like ci-ankrd52 exemplify lariat-derived structures, predominantly localized in the nucleus.^[30] Biogenesis of circRNAs involves alternative splicing events such as back-splicing, where a downstream splice donor joins an upstream splice acceptor. This can occur via direct back-splicing facilitated by complementary sequences in flanking introns (e.g., Alu repeats), often yielding ecircRNAs in the cytoplasm. Other pathways include lariat debranching, where exon-skipped lariat intermediates resist degradation by the DBR1 enzyme, leading to stable circular introns or exon-inclusive forms like ciRNAs and EIciRNAs. Intron excision circularization, driven by specific motifs (e.g., GU-rich and C-rich elements), allows intronic lariats to circularize without exonic involvement, typically producing nuclear ciRNAs.^[26] EcircRNAs dominate cytoplasmic abundance, while ciRNAs and EIciRNAs are primarily nuclear, reflecting their biogenesis constraints.^[30] Standardized nomenclature facilitates circRNA identification and comparison across studies. The circBase database assigns unique identifiers prefixed by species (e.g., "hsa" for Homo sapiens), followed by "circ_" and a numerical ID, such as hsa_circ_000001, linking to genomic coordinates and supporting datasets from high-throughput sequencing.^[31] This system unifies annotations from diverse origins, enabling precise referencing in research.^[32]

Size, Stability, and Cellular Localization

Circular RNAs (circRNAs) exhibit a characteristic size profile that distinguishes them from linear RNAs. Exonic circRNAs (ecircRNAs), derived primarily from back-spliced exons, typically range from 200 to 500 nucleotides (nt) in length, though some can extend up to 4 kilobases (kb). In contrast, circular intronic RNAs (ciRNAs) vary in size, often spanning hundreds to over 1000 nt depending on intron lengths. Unlike most linear messenger RNAs (mRNAs), circRNAs lack a poly(A) tail, which contributes to their resistance to poly(A)-dependent degradation pathways.^[33]^[1] The closed-loop structure of circRNAs confers exceptional stability compared to linear RNAs. This circular conformation protects them from exonuclease degradation, as demonstrated by their enrichment following treatment with RNase R, an enzyme that preferentially digests linear RNAs; circRNAs are typically enriched 10- to 100-fold relative to linear counterparts under these conditions.^[10] The half-life of ecircRNAs often exceeds 48 hours, in stark contrast to the average 10-hour half-life of mRNAs.^[34] Northern blot analyses further confirm this durability, showing circRNAs migrating more slowly than linear RNAs of equivalent length due to their covalently closed structure, which resists denaturation and enzymatic processing.^[10] These properties enable circRNAs to accumulate to higher levels in cells, facilitating sustained regulatory functions over extended periods.^[34] Subcellular localization of circRNAs varies by type and influences their functional roles. EcircRNAs predominantly reside in the cytoplasm, often associating with ribonucleoprotein (RNP) granules such as stress granules or processing bodies, where they can interact with microRNAs or proteins. Conversely, ciRNAs and exon-intron circRNAs (EIciRNAs) are primarily nuclear, where they associate with RNA polymerase II (Pol II) machinery, potentially modulating transcription. CircRNAs also display tissue-specific enrichment, with notable abundance in the brain and heart, reflecting their roles in neural and cardiac processes.^[35]^[3]^[36]

Molecular Functions

MicroRNA Sponging and Competing Endogenous RNA Activity

Circular RNAs (circRNAs) function prominently as microRNA (miRNA) sponges within the competing endogenous RNA (ceRNA) framework, where they harbor multiple miRNA response elements (MREs) to sequester miRNAs, thereby preventing their binding to target mRNAs and allowing derepression of those transcripts. This sponging activity is facilitated by the circRNAs' covalently closed structure, which confers resistance to exonuclease-mediated degradation and enables the stable accumulation of dense MRE clusters without the typical 5' cap or 3' poly-A tail vulnerabilities of linear RNAs.^[37] The paradigm was established with CDR1as (also termed ciRS-7), a brain-enriched circRNA derived from the CDR1 locus, which contains more than 70 conserved binding sites for miR-7, one of the most abundant miRNAs in neural tissues.^[37] By competitively binding miR-7, CDR1as inhibits its repressive effects on targets such as those involved in neuronal signaling, with the interaction validated through Argonaute (AGO) crosslinking immunoprecipitation sequencing (CLIP-seq) showing dense AGO-miR-7 occupancy on CDR1as.^[14] In vivo functional evidence comes from zebrafish embryos, where injection of synthetic CDR1as RNA mimics miR-7 knockdown phenotypes, resulting in sensorineural defects like impaired midbrain development due to miR-7 dysregulation and consequent target derepression.^[37] Additional examples illustrate the versatility of this mechanism across tissues and contexts. CircSRY, originating from the sex-determining region Y gene, acts as a sponge for miR-138 through multiple binding sites, reducing miR-138-mediated repression in reporter assays and altering cellular differentiation pathways.^[37] Similarly, circHIPK3, derived from the HIPK3 gene, sponges a repertoire of miRNAs—including miR-124, miR-152, and miR-29a—in proliferating cells, with CLIP-seq confirming direct interactions and luciferase assays demonstrating miRNA-dependent modulation of target expression in cancer models.^[38] The circular architecture uniquely supports this ceRNA role by permitting high-affinity, multivalent miRNA interactions without RNA turnover, as evidenced by pull-down experiments where circRNAs retain bound miRNAs longer than linear counterparts.^[37] Such sponging can lead to significant upregulation of target mRNA levels upon circRNA overexpression or miRNA sequestration, underscoring the regulatory scale in physiological networks.^[38]

Transcriptional and Post-Transcriptional Regulation

Circular RNAs (circRNAs) play significant roles in transcriptional regulation primarily through nuclear-localized forms such as circular intronic RNAs (ciRNAs) and exon-intron circRNAs (EIciRNAs). CiRNAs, derived solely from introns, associate with RNA polymerase II (Pol II) elongation machinery and promote cis-regulatory enhancement of parental gene transcription. For instance, ci-ankrd52, originating from the second intron of the ANKRD52 gene, accumulates at its transcription site and boosts ANKRD52 expression by interacting with Pol II, as demonstrated by RNA immunoprecipitation (RIP) experiments showing direct Pol II binding.^[39] Similarly, EIciRNAs, which retain unspliced introns, interact with U1 small nuclear ribonucleoprotein (snRNP) to form a complex that recruits Pol II to parental gene promoters, thereby enhancing transcription initiation and elongation. Depletion of specific EIciRNAs via RNA interference results in 20-50% reductions in parental gene expression levels, underscoring their regulatory impact.^[39] Beyond transcription, circRNAs influence post-transcriptional processes such as alternative splicing by serving as scaffolds for splicing factors. The muscleblind (MBL) protein binds to intronic sequences flanking its own pre-mRNA, promoting back-splicing to generate circMBL, which in turn sequesters excess MBL and fine-tunes its availability for linear splicing events. This autoregulatory loop maintains balanced MBL protein levels essential for neuronal and muscle development.^[22] N6-methyladenosine (m6A) modifications on circRNAs further modulate their post-transcriptional fate, affecting stability and subcellular localization. The m6A reader protein YTHDC1 recognizes these modifications and facilitates the nuclear export of m6A-modified circRNAs, enabling their cytoplasmic functions while preventing nuclear retention. This process influences circRNA half-life, with m6A promoting degradation via endonuclease recruitment in some contexts or enhancing stability through reader interactions.^[40]^[41] CircRNAs also regulate post-transcriptional events by sponging RNA-binding proteins (RBPs), distinct from their miRNA sponging activity. For example, circPABPN1 binds and sequesters the RBP HuR (also known as ELAVL1), preventing HuR from stabilizing and translating PABPN1 mRNA, thereby repressing polyadenylate-binding protein nuclear 1 (PABPN1) expression. Databases like CIRCpedia catalog numerous such circRNA-RBP interactions, revealing widespread RBP sequestration as a mechanism for fine-tuning gene expression across cell types.^[42] Certain circRNAs exhibit protein-coding potential through cap-independent translation mechanisms, such as internal ribosome entry sites (IRES) or m6A-modified cap-independent translation (IRES- or m6A-driven). For instance, circFBXW7, derived from the FBXW7 gene, translates a 21-kDa protein (FBXW7-185aa) that inhibits glioma cell proliferation by enhancing ubiquitination of c-Myc. This function has been validated in cancer models, highlighting circRNAs' role in producing functional peptides that modulate cellular processes. As of 2024, advances in ribosome profiling and mass spectrometry have identified hundreds of translatable circRNAs across species, expanding their regulatory repertoire beyond non-coding roles.^[1]^[43]

Biological Roles

Involvement in Immune Responses

Circular RNAs (circRNAs) play significant roles in modulating innate immune responses, particularly in antiviral defense mechanisms. In herpes simplex virus type 1 (HSV-1) infections, interferon-induced circRNAs, such as circRELL1, escape viral host shutoff and restrict viral replication by enhancing innate antiviral signaling. These circRNAs activate the RIG-I-like receptor (RLR) pathway, where RIG-I senses foreign circRNAs lacking N6-methyladenosine modifications, triggering type I interferon production and downstream antiviral gene expression. This activation promotes innate immunity without excessive inflammation, as demonstrated in studies showing that engineered circRNAs potently stimulate RIG-I-dependent responses to inhibit viral spread. Additionally, circRNAs can act as miRNA sponges to derepress immune genes; for instance, by sequestering miRNAs that suppress innate immunity activators, they upregulate interferon-stimulated genes during viral challenges. In cardiac injury, circCdr1as promotes anti-inflammatory M2 macrophage polarization via miR-7 and miR-671, as shown in 2025 studies.^[44] In inflammatory processes, circRNAs regulate macrophage polarization and cytokine production through key signaling pathways. The circRNA circPPM1F promotes M1 macrophage activation by sponging miR-134, thereby suppressing PPM1F translation and facilitating NF-κB pathway activation, which enhances pro-inflammatory cytokine release such as TNF-α and IL-6. Conversely, circCdr1as (also known as ciRS-7) modulates macrophage phenotypes toward an anti-inflammatory M2 state by interacting with miR-7 and miR-671, reducing excessive inflammation in contexts like cardiac injury. Knockdown of circCdr1as in macrophages leads to increased pro-inflammatory cytokine production, highlighting its regulatory role in balancing inflammatory responses. These mechanisms underscore circRNAs' involvement in fine-tuning NF-κB signaling to prevent chronic inflammation. CircRNAs also contribute to adaptive immunity, particularly in T and B cell functions. In B cells, circRNAs are enriched and influence activation and differentiation; for example, RNA-seq analyses of hematopoietic cells have identified over 100 immune-specific circRNAs differentially expressed in lymphoid lineages, supporting antibody production and immune memory. A notable example is circPTPN22, derived from the PTPN22 locus (a risk factor for rheumatoid arthritis and other autoimmune diseases), which sponges miR-4689 to upregulate S1PR1 expression, thereby modulating T-cell activation and proliferation. This circRNA's overexpression enhances T-cell receptor signaling, promoting adaptive responses but also contributing to autoimmune susceptibility when dysregulated. Studies from 2018 to 2023 using RNA-seq on immune cells have revealed hundreds of such circRNAs, with knockout models demonstrating reduced cytokine responses (e.g., IL-2 and IFN-γ) upon circRNA depletion, confirming their essential role in T-cell mediated immunity. Overall, through miRNA sponging of immune repressors and RIG-I enhancement, circRNAs integrate innate and adaptive arms of immunity for robust host defense.

Regulation of Development and Differentiation

Circular RNAs (circRNAs) play pivotal roles in embryonic development, where their expression often peaks during early stages to orchestrate key processes such as tissue specification and organogenesis. In human pre-implantation embryos, circRNA abundance dynamically varies from 28,774 to 190,008 copies per embryo across developmental stages, highlighting their temporal regulation during early embryogenesis. Similarly, in porcine models, circRNAs exhibit peak expression at embryonic day 60 (E60) in the brain, coinciding with rapid neural development, while in zebrafish embryos, circRNA profiles reveal stage-specific peaks distributed across embryogenesis, suggesting involvement in sequential patterning events like somitogenesis. For instance, comprehensive profiling in zebrafish identifies thousands of circRNAs with differential expression at various embryonic time points, implicating them in mesodermal segmentation and axial development. In cell differentiation, circRNAs contribute to lineage commitment and tissue specification, particularly in maintaining stem cell pluripotency and guiding differentiation trajectories. Single-cell RNA sequencing analyses across human and mouse tissues demonstrate that circRNAs display cell-type and developmental stage-specific expression patterns, with higher abundance in progenitor cells transitioning to differentiated states. In hematopoiesis, circRNAs such as those derived from antisense transcripts regulate stem cell maintenance by modulating RNA-binding protein interactions and competing endogenous RNA networks, ensuring balanced self-renewal and differentiation. Depletion studies further underscore their necessity, as CRISPR/Cas9-mediated knockdown of specific circRNAs, like circQKI in myogenic lineages, impairs differentiation efficiency, leading to prolonged progenitor states. During myogenesis, circZNF609 exemplifies circRNA function by promoting myoblast proliferation essential for muscle development. Expressed in both murine and human myoblasts, circZNF609 knockdown via siRNA reduces proliferation rates without affecting the linear ZNF609 mRNA, indicating a circRNA-specific role. This regulation occurs through cap-independent translation of circZNF609 into a protein that drives G1-S phase progression, as evidenced by delayed cell cycle entry in knockdown models. Additionally, circZNF609 associates with IGF2BP1 to enhance its own stability, amplifying proliferative signals during early myogenic commitment. In neurogenesis, circRNAs fine-tune neuronal differentiation and circuit formation, with prominent examples including circHOMER1 and CDR1as. CircHOMER1 regulates synaptic development and experience-dependent plasticity in the mouse visual cortex, where its depletion disrupts dendritic morphogenesis and excitatory synapse formation, as shown in 2025 studies. Single-cell RNA-seq reveals circHOMER1's enrichment in excitatory neurons, supporting its role in branching and connectivity during cortical specification. Likewise, CDR1as, highly expressed in brain tissues, modulates synaptic plasticity by sponging miR-7, and its CRISPR knockout in mice impairs excitatory transmission, delaying neuronal maturation and integration.^[45] Adipogenesis involves circRNAs that interact with epigenetic regulators to promote preadipocyte differentiation into mature adipocytes. CircFIRRE, derived from the FIRRE locus, emerges as a highly abundant circRNA during human embryonic stem cell differentiation toward adipogenic lineages, correlating with enhanced lipid accumulation and metabolic reprogramming. Relatedly, circSAMD4A acts as a miR-138-5p sponge to upregulate EZH2, a histone methyltransferase that represses anti-adipogenic genes, thereby accelerating differentiation in obesity-associated models. Experimental evidence from CRISPR-based knockdowns confirms these roles; for example, targeting circZNF609 in myoblasts or CDR1as in neurons delays differentiation by 2-3 days, as measured by marker gene expression and morphological assays. Complementary single-cell RNA-seq datasets across developmental stages further validate stage-specific circRNA upregulation, such as in midbrain dopaminergic progenitors, where circRNAs like those regulating neuron size and migration peak during specification.

Implications in Disease

Neurological and Neurodegenerative Disorders

Circular RNAs (circRNAs) have emerged as key regulators in the pathogenesis of Alzheimer's disease (AD), with dysregulation observed in post-mortem brain tissues and biofluids. Genome-wide RNA sequencing studies have identified 147 differentially expressed circRNAs in AD brains across regions like the superior temporal lobe and parahippocampal gyrus, with fold changes ≥1.15-fold compared to healthy controls.^[46] For instance, circHDAC9 expression is significantly decreased in the sera and brains of AD patients and mouse models, leading to reduced sponging of miR-138.^[47] This downregulation allows miR-138 to inhibit SIRT1, thereby promoting amyloid-β (Aβ) accumulation and mitochondrial dysfunction; overexpression of circHDAC9 in vitro suppresses excessive Aβ production by enhancing SIRT1 activity.^[47] In APP/PS1 mouse models of AD, knockdown of circCwc27—a circRNA upregulated in AD—reduces Aβ plaque load by approximately 40% in the hippocampus and improves spatial learning and memory performance.^[48] In Parkinson's disease (PD), circRNAs contribute to α-synuclein pathology through microRNA sponging mechanisms. circSNCA, derived from the SNCA gene, is upregulated in PD models and acts as a sponge for miR-7, which normally binds the 3' untranslated region of SNCA mRNA to suppress its translation.^[49] This interaction stabilizes SNCA mRNA, leading to increased α-synuclein protein levels and enhanced neuronal apoptosis; treatment with pramipexole downregulates circSNCA, thereby restoring miR-7 activity, reducing cell death, and promoting autophagy in PD cell models.^[49] Post-mortem RNA-seq analyses of PD brains confirm elevated circSNCA expression, correlating with disease severity.^[50] Beyond major neurodegenerative disorders, circRNAs influence other neurological conditions, including epilepsy and schizophrenia. Transcriptomic studies indicate circRNA dysregulation in these disorders, potentially affecting neuronal excitability and synaptic plasticity.^[51] circRNAs also play roles in neuronal repair mechanisms, such as axon regeneration following injury. Neuronal circRNAs are enriched and stable in exosomes, facilitating intercellular communication in the central nervous system; for example, circ-Spidr promotes axon regrowth in dorsal root ganglion neurons after peripheral nerve injury by modulating regenerative pathways.^[52] In AD contexts, circRNAs from brain tissue exhibit disease-specific profiles, highlighting their potential as biomarkers for monitoring neurodegeneration.^[53] These findings underscore the therapeutic promise of targeting circRNAs to mitigate synaptic loss and protein aggregation in neurological disorders.

Cardiovascular, Metabolic, and Oncological Conditions

Circular RNAs (circRNAs) play significant roles in cardiovascular diseases, particularly in cardiac hypertrophy and myocardial infarction (MI). Studies have identified differentially expressed circRNAs in MI models, suggesting their involvement in inflammation, apoptosis, and fibrosis following ischemia.^[54] For instance, circFndc3b has been shown to modulate cardiac repair post-MI by regulating endothelial cell proliferation and angiogenesis.^[55] In renal and metabolic disorders, circRNAs contribute to fibrosis and lipid dysregulation. circACTR2 promotes renal fibrosis by sponging miR-561 to activate the NLRP3 inflammasome in kidney cells.^[56] In diabetic nephropathy, a complication of metabolic syndrome, circRNAs serve as potential diagnostic markers, with expression changes correlating to disease severity and renal function decline.^[57] Oncological conditions feature prominent circRNA dysregulation across multiple cancers. In hepatocellular carcinoma (HCC), circRNAs drive tumor progression through competing endogenous RNA activity. Similarly, in colorectal cancer, circHIPK3 enhances cell proliferation and invasion by sponging miR-7.^[58] Pan-cancer analyses from the 2020s, integrating data from sources like The Cancer Genome Atlas (TCGA), have cataloged over 1,000 oncogenic circRNAs, revealing conserved networks where circRNAs sponge tumor-suppressive miRNAs to promote proliferation and metastasis across tumor types.^[59] CircRNAs hold diagnostic promise as circulating biomarkers in these conditions. In MI, plasma levels of specific circRNAs, such as circ_0049271, achieve high discriminatory accuracy with an area under the curve (AUC) greater than 0.85 for early detection, outperforming some traditional markers.^[60] Therapeutic targeting of circRNAs also shows efficacy; for example, siRNA-mediated knockdown of oncogenic circRNAs like circRNA-SORE in sorafenib-resistant HCC xenografts restores sorafenib sensitivity and reduces tumor growth, demonstrating potential for precision oncology.^[61] TCGA-integrated studies further validate these networks, linking circRNA expression to clinical outcomes in metabolic and oncological diseases.^[62]

Evolutionary Perspectives

Conservation Across Species

Circular RNAs (circRNAs) exhibit varying degrees of conservation across species, reflecting the evolutionary persistence of their biogenesis mechanisms and functional elements. The back-splicing process that generates most eukaryotic circRNAs relies on the spliceosome, a conserved splicing machinery universal among eukaryotes, which enables the covalent joining of splice donor and acceptor sites in reverse order.^[63] In mammals, this is often facilitated by Alu repeats providing intron complementarity, while analogous repetitive elements and base-pairing motifs support back-splicing in non-mammalian species such as Drosophila, where circRNAs are highly enriched and conserved across fly species. This shared dependence on canonical splicing components underscores the ancient origins of circRNA formation, predating major eukaryotic divergences. At the sequence level, certain circRNAs display strong conservation, particularly in vertebrates. For instance, the circRNA CDR1as (also known as ciRS-7), a well-studied miRNA sponge, is highly conserved across mammals, with its core sequence and multiple miR-7 binding sites preserved in human, mouse, and other vertebrates, though the back-splice junctions themselves show less conservation than the miRNA target sites.^[64] Comparative analyses reveal that while global circRNA repertoires evolve rapidly, a subset of circRNAs—often those with regulatory functions—exhibits appreciable sequence conservation between closely related species like human and mouse, with orthologous circRNAs comprising approximately 10-20% of identified repertoires in shared tissues.^[65] Back-spliced circRNAs are abundant across eukaryotic kingdoms beyond animals, including plants and fungi, but are absent in prokaryotes due to the lack of spliceosomes; however, other circular RNAs, such as circular 23S rRNAs, are abundant in archaeal ribosomes across diverse lineages, suggesting ancient circular RNA structures in prokaryotes.^[66] In plants, thousands of circRNAs have been identified in species like Arabidopsis thaliana, often derived from exonic regions involved in stress responses and development, demonstrating back-splicing via intron pairing without reliance on mammalian-specific repeats.^[67] Similarly, in fungi such as Magnaporthe oryzae, over 8,000 circRNAs arise from back-splicing during mycelial growth, indicating conserved biogenesis signals in this kingdom.^[68] Evolutionary studies highlight the persistence of intron pair complementarity as a key biogenesis signal, with motifs enabling circularization conserved over hundreds of millions of years in eukaryotic lineages, and circRNA exons showing elevated sequence conservation compared to non-circRNA exons from the same genes, suggestive of functional constraints.^[69] Recent comparative genomics from 2016 to 2023, integrating datasets across vertebrates, further confirm that 10-20% of circRNAs are orthologous between human and mouse, with higher rates in brain and heart tissues, emphasizing species-specific yet functionally preserved roles.^[70]^[69]

Role in RNA World Hypothesis and Viroids

Circular RNAs (circRNAs) have been proposed as potential relics from the precellular RNA world, where RNA molecules served dual roles as genetic material and catalysts prior to the emergence of DNA and proteins. Their covalently closed structure confers exceptional stability against exonucleases, a property that would have been advantageous in primitive, error-prone self-replicating systems, enabling the formation of self-sustaining RNA networks capable of Darwinian evolution. This stability, combined with the absence of free ends, mirrors the requirements for efficient replication in an RNA-dominated era, positioning circRNAs as plausible survivors of early life forms.^[71]^[72] Viroids, the smallest known infectious agents, exemplify non-coding circular RNAs and reinforce these connections to ancient RNA-based systems. These plant pathogens consist of single-stranded, circular RNAs typically 250-400 nucleotides in length that lack protein-coding capacity and replicate using host RNA polymerases. The potato spindle tuber viroid (PSTVd), the first identified viroid, was discovered in 1971 by Theodor O. Diener through studies on potato disease etiology, revealing its unconventional nature as a naked RNA replicator.^[73]^[74] Parallels between viroids and cellular circRNAs highlight shared mechanisms for persistence, particularly in circularization and durability. Viroids in the family Avsunviroidae employ hammerhead ribozymes—self-cleaving RNA motifs—for processing linear precursors into mature circular forms during replication, a process that enhances their resistance to degradation. Cellular circRNAs, while formed via backsplicing rather than ribozymes, exhibit analogous exonuclease resistance due to their closed loops, suggesting they may mimic viroid-like strategies for long-term RNA persistence in modern cells.^[75]^[71] Some hypotheses suggest that viroid-like circular RNAs may represent relics from the RNA world, potentially protecting early RNA genomes from degradation. Recent 2020s studies on synthetic circRNAs have explored their properties through in vitro assembly and testing, demonstrating enhanced durability and protein expression that echo prebiotic RNA dynamics. These experiments support the idea that circular forms could have facilitated genome protection and replication in early progenitors.^[72]^[76] Supporting evidence includes the in vitro demonstration of viroid replication via a rolling-circle mechanism, where circular templates generate multimeric intermediates that are cleaved and ligated to produce new circles, a process reliant on host enzymes but initiated by RNA self-processing. This mechanism underscores the viroid's durability, akin to circRNA resistance to RNases, which allows both to evade typical RNA turnover pathways and persist in diverse conditions.^[74]^[71]

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