Search Results (55)

Transposable elements (TEs), once regarded as genomic “junk,” are now recognized as powerful regulators of gene expression, genome stability, and innate immunity. In the context of neurodegeneration, particularly Amyotrophic Lateral Sclerosis (ALS), accumulating evidence implicates TEs as active contributors to disease pathogenesis. ALS is a fatal motor neuron disease with both sporadic and familial forms, linked to genetic, epigenetic, and environmental factors. While coding mutations explain a subset of cases, advances in long-read sequencing and epigenomic profiling have unveiled the profound influence of non-coding regions—especially retrotransposons such as LINE-1, Alu, and SVA—on ALS onset and progression. TEs may act through multiple mechanisms: generating somatic mutations, disrupting chromatin architecture, modulating transcriptional networks, and triggering sterile inflammation via innate immune pathways like cGAS-STING. Their activity is normally repressed by epigenetic regulators, including DNA methylation, histone modifications, and RNA interference pathways; however, these controls are compromised in ALS. Taken together, these insights underscore the translational potential of targeting transposable elements in ALS, both as a source of novel biomarkers for patient stratification and disease monitoring, and as therapeutic targets whose modulation may slow neurodegeneration and inflammation. This review synthesizes the current knowledge of TE biology in ALS; integrates findings across molecular, cellular, and systems levels; and explores the therapeutic potential of targeting TEs as modulators of neurodegeneration. Full article

Cervical cancer remains the fourth most common cancer among women globally, disproportionately impacting low- and middle-income countries despite the existence of HPV vaccines. While DNA methylation has been studied extensively as a biomarker, other epigenetic mechanisms remain underexplored. This scoping review aims to report such underexplored epigenetic biomarkers linked to cervical cancer, shifting the focus beyond global nuclear DNA methylation. Literature searches were performed using Google Scholar via Publish or Perish software including studies published until January 2025. Our review focused on mitochondrial DNA, non-coding RNA, histone modifications, and repetitive elements. Mitochondrial DNA methylation has been proposed as a cervical cancer biomarker, although supporting evidence is limited. Histone modifications are more consistently reported to be involved both in cervical cancer onset and aggressiveness. Similarly, aberrant expression of lncRNAs, circRNAs, miRNAs, and piRNAs has been associated with poor prognosis. Finally, hypomethylation in repetitive elements such as LINE-1 and Alu is often observed in cervical cancer, contributing to genomic instability and tumorigenesis. Highlighting these alternative epigenetic mechanisms, our review emphasizes the importance of expanding biomarker discovery beyond the traditional nuclear DNA methylation. Understanding these mechanisms may improve early detection and personalized disease management strategies for cervical cancer. Full article

Long- or post-COVID-19 syndrome, which is also designated by WHO as Post COVID-19 Condition (PCC), is characterized by the persistent symptoms that remain after recovery from SARS-CoV-2 infection. A worldwide consortium of Long COVID-19 Host Genetics Initiative (Long COVID-19 HGI) identified an SNP rs9367106 (G>C; chr6:41,515,652, GRCh38, p = 1.76 × 10⁻¹⁰, OR = 1.63, 95% CI: 1.40–1.89) that is associated with PCC. Unraveling the functional significance of this SNP is of prime importance to understanding the development of the PCC phenotypes and their therapy. Here, in Silico, I explored how the risk allele of this SNP alters the functional mechanisms and molecular pathways leading to the development of PCC phenotypes. Bioinformatic methods include physical interactions using HI-C and Chia-PET analysis, Transcription Factors (TFs) binding ability, RNA structure modeling, epigenetic, and pathway analysis. This SNP resides within two long RNA genes, LINC01276 and FOXP4-AS1, and is located at ~31 kb upstream of a transcription factor FOXP4. This DNA region, including this SNP, physically interacts with FOXP4-AS1 and FOXP4, implying that this regulatory SNP could alter the normal cellular function of FOXP4-AS1 and FOXP4. Furthermore, rs9367106 is in eQTL with the FOXP4 gene in lung tissue. rs9367106 carrying DNA sequences act as distant enhancers and bind with several transcription factors (TFs) including YY1, PPAR-α, IK-1, GR-α, and AP2αA. The G>C transition extensively modifies the RNA structure that may affect the TF bindings and enhancer functions to alter the interactions and functions of these RNA molecules. This SNP also includes an ALU/SINE sequence and alteration of which by the G>C transition may prevent IFIH1/MDA5 activation, leading to suppression of host innate immune responses. LINC01276 targets the MED20 gene that expresses mostly in brain tissues, associated with sleep disorders and basal ganglia abnormalities similar to some of the symptoms of PCC phenotypes. Taken together, G>C transition of rs9367601 may likely alter the function of all three genes to explain the molecular basis of developing the long-term symptomatic abnormalities in the lungs and brain observed after COVID-19 recovery. Full article

Paraspeckles are nuclear membraneless structures composed of a long non-coding RNA, Nuclear-Enriched-Abundant-Transcript-1, and RNA-binding proteins, which associate with numerous mRNAs. It is therefore believed that their cellular function is to sequester in the nucleus their associated proteins and/or target mRNAs. However, little is known about the molecular determinant in mRNA targets that allows their association to paraspeckles, except that inverted repeats of Alu sequences (IRAlu) present in the 3′UTR of mRNAs may allow this association. While in a previous study we established the list of paraspeckle target RNAs in a rat pituitary cell line, we did not find, however, inverted repeated SINEs, the rat equivalent of primate IRAlus in 3′UTR of these RNAs. By developing a candidate gene strategy, we selected a paraspeckle target gene, namely calreticulin mRNA, and we searched for other potential RNA recruitment elements in its 3′UTR, since 3′UTRs usually contain the sequence recognition for nuclear localization. We found a 15-nucleotide sequence surrounded in 5′ by a C-rich sequence, which is present as a tandem repeat in the 3′UTR of this mRNA and which is involved in the nuclear retention by paraspeckles. As shown by mass spectrometry analysis, 6 proteins bound to the 15-nucleotide sequence are paraspeckle proteins and constitute, therefore, bridging proteins between paraspeckles and target mRNAs. Full article

RNA polymerase III (Pol III) transcribes a broad spectrum of non-coding RNAs, including transfer RNAs (tRNAs), 5S ribosomal RNA (5S rRNA), U6 small nuclear RNA (U6 snRNA), and a range of regulatory RNAs (7SK, 7SL, RMRP, RPPH1, Y RNA, vault RNA, Alu, BC200, snaR, and nc886). These RNAs are integral to fundamental cellular processes, including transcription and translation, RNA processing and stability, and cytoplasmic protein targeting. Among them, tRNA-derived small RNAs (tsRNAs) have recently emerged as critical regulators across a wide array of biological contexts. Increasing evidence links the dysfunction of Pol III transcripts to human diseases, particularly genetic disorders and cancer. In this review, we provide a comprehensive overview of Pol III-transcribed RNAs, their biogenesis and regulatory mechanisms, and their biological functions. We also explore emerging insights into the disease relevance of Pol III-transcribed RNAs and discuss their potential implications for future research and therapeutic development. Full article

Transposable elements (TEs) make up around half of the human genome. Their transcription is repressed in most somatic cells to maintain genome integrity and function. The repression is chiefly maintained by a combination of epigenetic modifications such as DNA methylation and histone modifications. However, recent research suggests that liver steatosis is associated with extensive changes to the hepatocyte epigenome. Furthermore, studies in mice have reported diet- and drug-induced changes to TE transcript levels in liver. The confirmation of these effects in human liver has not previously been undertaken. Here, we examined TE transcription in liver tissue from three patient cohorts with histologically confirmed liver steatosis caused by alcohol consumption or metabolic dysfunction. The quantitation of the number of transcripts with TE-homology in RNA-Seq data from a cohort of 90 bariatric surgery patients with metabolic dysfunction-associated steatotic liver disease (MASLD) revealed a trend for the reduction in TEs of all classes due to increasing steatosis, but no effect of fibrosis. This pattern was also present in a separate cohort of MASLD and HCC patients, as RT-qPCR also showed a reduction in Alu element transcripts in advanced steatosis, but again, no effect of fibrosis. Contrastingly, in a cohort of alcohol-related liver disease patients, the reduction in LINE-1 transcripts was associated with either increased steatosis or increased fibrosis. Moreover, the examination of LINE-1 DNA methylation levels in the MASLD and HCC cohort indicated that DNA methylation was also negatively associated with LINE-1 transcription in MASLD. This study suggests that TE transcript levels in human liver are slightly reduced by steatosis, that DNA methylation is an influential epigenetic regulator of LINE-1 retrotransposon transcription in steatosis, and that Alu transcript levels in background liver could be a new biomarker for HCC in cirrhotic and non-cirrhotic MASLD. Full article

The double-stranded RNA editing enzyme ADAR1 connects two forms of genetic programming, one based on codons and the other on flipons. ADAR1 recodes codons in pre-mRNA by deaminating adenosine to form inosine, which is translated as guanosine. ADAR1 also plays essential roles in the immune defense against viruses and cancers by recognizing left-handed Z-DNA and Z-RNA (collectively called ZNA). Here, we review various aspects of ADAR1 biology, starting with codons and progressing to flipons. ADAR1 has two major isoforms, with the p110 protein lacking the p150 Zα domain that binds ZNAs with high affinity. The p150 isoform is induced by interferon and targets ALU inverted repeats, a class of endogenous retroelement that promotes their transcription and retrotransposition by incorporating Z-flipons that encode ZNAs and G-flipons that form G-quadruplexes (GQ). Both p150 and p110 include the Zβ domain that is related to Zα but does not bind ZNAs. Here we report strong evidence that Zβ binds the GQ that are formed co-transcriptionally by ALU repeats and within R-loops. By binding GQ, ADAR1 suppresses ALU-mediated alternative splicing, generates most of the reported nonsynonymous edits and promotes R-loop resolution. The recognition of the various alternative nucleic acid conformations by ADAR1 connects genetic programming by flipons with the encoding of information by codons. The findings suggest that incorporating G-flipons into editmers might improve the therapeutic editing efficacy of ADAR1. Full article

Circular RNAs (circRNAs) are a class of unique transcripts characterized by a covalently closed loop structure, which differentiates them from conventional linear RNAs. The formation of circRNAs occurs co-transcriptionally and post-transcriptionally through a distinct type of splicing known as back-splicing, which involves the formation of a head-to-tail splice junction between a 5′ splice donor and an upstream 3′ splice acceptor. This process, along with exon skipping, intron retention, cryptic splice site utilization, and lariat-driven intron processing, results in the generation of three main types of circRNAs (exonic, intronic, and exonic–intronic) and their isoforms. The intricate biogenesis of circRNAs is regulated by the interplay of cis-regulatory elements and trans-acting factors, with intronic Alu repeats and RNA-binding proteins playing pivotal roles, at least in the formation of exonic circRNAs. Various hypotheses regarding pathways of circRNA turnover are forwarded, including endonucleolytic cleavage and exonuclease-mediated degradation; however, similarly to the inconclusive nature of circRNA biogenesis, the process of their degradation and the factors involved remain largely unclear. There is a knowledge gap regarding whether these processes are guided by universal pathways or whether each category of circRNAs requires special tools and particular mechanisms for their life cycles. Understanding these factors is pivotal for fully comprehending the biological significance of circRNAs. This review provides an overview of the various pathways involved in the biogenesis and degradation of different types of circRNAs and explores key factors that have beneficial or adverse effects on the formation and stability of these unique transcripts in higher eukaryotes. Full article

Background/Objectives: The highly polymorphic Major Histocompatibility Complex (MHC) genomic region, located on the short arm of chromosome 6, is implicated genetically in Parkinson’s disease (PD), a progressive neurodegenerative disorder with motor and non-motor symptoms. Previously, we reported significant associations between SINE-VNTR-Alu (SVA) expression quantitative trait loci (eQTLs) and Human Leucocyte Antigen (HLA) class I genotypes in PD. In this study, we aimed to evaluate SVA associations and their regulatory effects on transposable element (TE) transcription in the MHC class I region. Methods: Transcriptome data from the peripheral blood cells of 1530 individuals in the Parkinson’s Progression Markers Initiative (PPMI) cohort were reanalyzed for TE and gene expression using publicly available bioinformatics tools, including Salmon and Matrix-eQTL. Results: Four structurally polymorphic SVAs regulated the transcription of 18 distinct clusters of 235 TE loci, comprising LINEs (33%), SINEs (19%), LTRs (35%), and ancient transposon DNA elements (12%) located near HLA genes. The transcribed TEs were predominantly short, with an average length of 445 nucleotides. The regulatory effects of these SVAs varied significantly in terms of TE types, numbers, and transcriptional activation or repression. The SVA-regulated TE RNAs in blood cells appear to function as enhancer-like elements, differentially influencing the expression of HLA class I genes, non-HLA genes, and noncoding RNAs. Conclusions: These findings highlight the roles of SVAs and their associated TEs in the complex regulatory networks governing coding and noncoding gene expression in the MHC class I region, with potential implications for immune function and disease susceptibility. Full article

Background/Objective: Large genomic rearrangements of PALB2 gene, particularly deletions and duplications, have been linked to hereditary breast–ovarian cancer. Our research specifically focuses on delineating the intronic breakpoints associated with rearrangements of PALB2 exon 11, which is crucial for understanding the mechanisms underlying these genomic changes in patients with hereditary breast and ovarian syndrome. Methods: By using next-generation sequencing, we identified one duplication and three deletions of PALB2 exon 11, confirmed by Multiplex Ligation-Dependent Probe Amplification analysis. To assess the impact on transcription and potential splicing issues, reverse-transcription PCR was performed on patients’ RNA. For the detailed characterization of intronic breakpoints, the primer walking approach and long-range PCR were implemented, followed by Sanger sequencing. Results: Our analysis revealed a tandem duplication of 5134 base pairs (bp) mediated by AluY repeats located in introns 10 and 11, respectively. Moreover, identical deletions were identified in three unrelated patients, encompassing an approximate 8050 bp region mediated by AluSx elements. Both genomic alterations resulted in a truncated PALB2 protein due to the introduction of a premature stop codon. Conclusions: This study underscores the remarkable instability of intronic regions flanking exon 11 of PALB2 and identifies a previously unreported hotspot involving Alu repeats with very high sequence homology in introns 10 and 11 of the gene. Our findings suggest avenues for further research, such as investigating the prevalence of similar genomic rearrangements in larger cohorts and exploring functional studies to understand how these alterations contribute to hereditary breast cancer pathogenesis. Full article

SINE-VNTR-Alu (SVA) retrotransposons can regulate expression quantitative trait loci (eQTL) of coding and noncoding genes including transposable elements (TEs) distributed throughout the human genome. Previously, we reported that expressed SVAs and human leucocyte antigen (HLA) class II genotypes on chromosome 6 were associated significantly with Parkinson’s disease (PD). Here, our aim was to follow-up our previous study and evaluate the SVA associations and their regulatory effects on the transcription of TEs within the HLA class II genomic region. We reanalyzed the transcriptome data of peripheral blood cells from the Parkinson’s Progression Markers Initiative (PPMI) for 1530 subjects for TE and gene RNAs with publicly available computing packages. Four structurally polymorphic SVAs regulate the transcription of 20 distinct clusters of 235 TE loci represented by LINES (37%), SINES (28%), LTR/ERVs (23%), and ancient transposon DNA elements (12%) that are located in close proximity to HLA genes. The transcribed TEs were mostly short length, with an average size of 389 nucleotides. The numbers, types and profiles of positive and negative regulation of TE transcription varied markedly between the four regulatory SVAs. The expressed SVA and TE RNAs in blood cells appear to be enhancer-like elements that are coordinated differentially in the regulation of HLA class II genes. Future work on the mechanisms underlying their regulation and potential impact is essential for elucidating their roles in normal cellular processes and disease pathogenesis. Full article

The most common form of hereditary spastic paraplegia (HSP), SPG4 is caused by single nucleotide variants and microrearrangements in the SPAST gene. The high percentage of multi-exonic deletions or duplications observed in SPG4 patients is predisposed by the presence of a high frequency of Alu sequences in the gene sequence. In the present study, we analyzed DNA and RNA samples collected from patients with different microrearrangements in SPAST to map gene breakpoints and evaluate the mutation mechanism. The study group consisted of 69 individuals, including 50 SPG4 patients and 19 healthy relatives from 18 families. Affected family members from 17 families carried varying ranges of microrearrangements in the SPAST gene, while one individual had a single nucleotide variant in the 5′UTR of SPAST. To detect the breakpoints of the SPAST gene, long-range PCR followed by sequencing was performed. The breakpoint sequence was detected for five different intragenic SPAST deletions and one duplication, revealing Alu-mediated microhomology at breakpoint junctions resulting from non-allelic homologous recombination in these patients. Furthermore, SPAST gene expression analysis was performed using patient RNA samples extracted from whole blood. Quantitative real-time PCR tests performed in 14 patients suggest no expression of transcripts with microrearrangements in 5 of them. The obtained data indicate that nonsense-mediated decay degradation is not the only mechanism of hereditary spastic paraplegia in patients with SPAST microrearrangements. Full article

Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology. Full article

Complex structural chromosome abnormalities such as chromoanagenesis have been reported in acute myeloid leukemia (AML). They are usually not well characterized by conventional genetic methods, and the characterization of chromoanagenesis structural abnormalities from short-read sequencing still presents challenges. Here, we characterized complex structural abnormalities involving chromosomes 2, 3, and 7 in an AML patient using an integrated approach including CRISPR/Cas9-mediated nanopore sequencing, mate pair sequencing (MPseq), and SNP microarray analysis along with cytogenetic methods. SNP microarray analysis revealed chromoanagenesis involving chromosomes 3 and 7, and a pseudotricentric chromosome 7 was revealed by cytogenetic methods. MPseq revealed 138 structural variants (SVs) as putative junctions of complex rearrangements involving chromosomes 2, 3, and 7, which led to 16 novel gene fusions and 33 truncated genes. Thirty CRISPR RNA (crRNA) sequences were designed to map 29 SVs, of which 27 (93.1%) were on-target based on CRISPR/Cas9 crRNA nanopore sequencing. In addition to simple SVs, complex SVs involving over two breakpoints were also revealed. Twenty-one SVs (77.8% of the on-target SVs) were also revealed by MPseq with shared SV breakpoints. Approximately three-quarters of breakpoints were located within genes, especially intronic regions, and one-quarter of breakpoints were intergenic. Alu and LINE repeat elements were frequent among breakpoints. Amplification of the chromosome 7 centromere was also detected by nanopore sequencing. Given the high amplification of the chromosome 7 centromere, extra chromosome 7 centromere sequences (tricentric), and more gains than losses of genomic material, chromoanasynthesis and chromothripsis may be responsible for forming this highly complex structural abnormality. We showed this combination approach’s value in characterizing complex structural abnormalities for clinical and research applications. Characterization of these complex structural chromosome abnormalities not only will help understand the molecular mechanisms responsible for the process of chromoanagenesis, but also may identify specific molecular targets and their impact on therapy and overall survival. Full article

While studies demonstrating the expression of repetitive elements (REs) in psoriatic skin using RNA-seq have been published before, not many studies have focused on the genome-wide expression patterns using larger cohorts. This study investigated the transcriptional landscape of differentially expressed REs in lesional and non-lesional skin from two previously published large datasets. We observed significant differential expression of REs in lesional psoriatic skin as well as the skin of healthy controls. Significant downregulation of several ERVs, HERVs (including HERV-K) and LINEs was observed in lesional psoriatic skin from both datasets. The upregulation of a small subset of HERV-Ks and Alus in lesional psoriatic skin was also reported. An interesting finding from this expression data was the significant upregulation and overlapping of tRNA repetitive elements in lesional and non-lesional psoriatic skin. The data from this study indicate the potential role of REs in the immunopathogenesis of psoriasis. The expression data from the two independent large study cohorts are powerful enough to confidently verify the differential expression of REs in relation to psoriatic skin pathology. Further studies are warranted to understand the functional impact of these repetitive elements in psoriasis pathogenesis, thereby expanding their significance as a potential targeting pathway for the disease treatment of psoriasis and other inflammatory diseases. Full article