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PubMed2026

Lipid Metabolism-related lncRNA Model Identifies AC026412.3 as a Driver of Fatty Acid β-oxidation in Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Dysregulated lipid metabolism contributes to hepatocellular carcinoma (HCC) progression, but the prognostic value and mechanistic roles of lipid metabolism-related long noncoding RNAs (LRLs) remain insufficiently characterized. This study aimed to construct and validate an LRL-based prognostic model and to investigate the biological function and metabolic mechanism of AC026412.3 in HCC. METHODS: Transcriptomic and clinical data from the The Cancer Genome Atlas Liver Hepatocellular Carcinoma cohort were analyzed to identify LRLs based on their correlation with curated lipid metabolism genes. Differential expression, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a prognostic signature, which was evaluated using Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) analyses. Functional enrichment analyses Gene Ontology [GO], Kyoto Encyclopedia of Genes and Genomes [KEGG] and gene set enrichment analysis [GSEA], mutation profiling, tumor mutational burden, immune infiltration estimation, and consensus clustering were applied to characterize associated features. A key LRL was identified through integrated bioinformatic screening and prioritization. Its biological role was assessed by quantitative reverse transcription polymerase chain reactionq (RT-PCR), western blotting, BODIPY staining, colony formation, Transwell assays, and xenograft models. RNA sequencing followed by pathway enrichment analysis was conducted to explore underlying mechanisms. RESULTS: A three-LRL signature (AL031985.3, NRAV, and AC026412.3) stratified HCC patients into distinct risk groups with significantly different survival outcomes and demonstrated independent prognostic value. AC026412.3 was markedly upregulated in HCC and associated with poor prognosis. Functional assays demonstrated that AC026412.3 promoted proliferation, invasion, and tumor growth while reducing lipid accumulation. Mechanistically, AC026412.3 upregulated solute carrier family 22 member 5 (SLC22A5), enhanced fatty acid β-oxidation, and increased adenosine triphosphate (ATP) production, thereby driving metabolic reprogramming. CONCLUSIONS: This study establishes a robust LRL-based prognostic model and identifies AC026412.3 as a key regulator of lipid metabolic reprogramming via the SLC22A5-fatty acid β-oxidation axis, highlighting its potential as a biomarker and therapeutic target in HCC.

HCC↗

PubMedDate not supplied

Effective resistance to potyvirus infection conferred by expression of antisense RNA in transgenic plants.

Approximately 660 nt including the carboxy-terminal portion of the bean yellow mosaic potyvirus (BYMV) coat protein gene, complete 3' noncoding sequence and a short poly(A) tract were introduced to produce antisense RNA in transgenic Nicotiana benthamiana. Original (R0) transformants were selfed, and homozygous second generation (R2) populations challenged with infected sap, purified virus, or viral RNA. One transgenic line of 10 examined was extremely resistant to infection by mechanical inoculation of 100 micrograms/ml BYMV or 50 micrograms/ml BYMV RNA (the highest concentrations tested); no virus could be detected in inoculated leaves of this line. Nine other lines were systemically infected when inoculated with BYMV or BYMV RNA, with initial symptoms indistinguishable from those in nontransgenic plants. One of these lines subsequently developed reduced symptoms and then symptomless, virus-free leaves (complete recovery from BYMV infection), while other lines produced leaves with reduced symptoms and reduced virus titer compared to the controls (partial recovery). No transgenic lines had resistance to infection, nor recovery from symptom expression, following inoculation with pepper mottle or turnip mosaic potyviruses. Antisense RNA from 3' regulatory regions can confer multiple degrees of resistance to potyviruses, including extreme resistanc to infection, presumably by interference in virus replication.

Base Sequence↗

PubMed1990

Isolation of cDNAs coding for three different forms of liver microsomal cytochrome P-450 from polychlorinated biphenyl-treated beagle dogs.

Three different cDNA clones, namely DM1-1, Dah1, and Dah2, encoding hepatic cytochrome P-450, were isolated from a cDNA library in lambda gt11 constructed from liver RNA of polychlorinated biphenyl-treated beagle dogs. DM1-1 was 1857 base pairs (bp) long and encoded a polypeptide of 457 residues. Dah1 was 2394 bp long and contained an entire coding region for 524 amino acid residues. In addition, Dah2 was 1623 bp long and had an open reading frame consisting of 503 amino acid residues, although it lacked the translational initiation codon. Judging from the similarity of the nucleotide and amino acid sequences, forms of cytochrome P-450 encoded by DM1-1, Dah1, and Dah2 were judged to belong to the P450IIC, P450IA1, and P450IA2 subfamilies, respectively. Northern blot analysis of RNA from various tissues, using the specific 3' noncoding regions of Dah1 and Dah2 as probes, indicated that mRNAs for P-450(Dah1) and P-450(Dah2) were not detectable in tissues from untreated dogs, except for P-450(Dah2) in livers. Polychlorinated biphenyl induced both mRNAs in liver, kidney, and lung, especially in the kidney.

Amino Acid Sequence↗

PubMed1986

Cloning of Drosophila choline acetyltransferase cDNA.

Choline acetyltransferase (EC 2.3.1.6) is the biosynthetic enzyme for the neurotransmitter acetylcholine. To isolate choline acetyltransferase cDNA clones, a cDNA library was constructed from poly(A)+ RNA of Drosophila melanogaster heads, these being one of the richest known sources of the enzyme. By screening the cDNA library with a mixture of three different monoclonal antibodies to Drosophila choline acetyltransferase, we isolated 14 positive clones. Only 1 of these clones was identified to be a Drosophila choline acetyltransferase cDNA clone based on the following evidence. (i) The amino acid sequence deduced from the nucleotide sequence of the cDNA insert completely corresponded to that of several tryptic peptides from choline acetyltransferase. (ii) The cDNA insert hybridized specifically to only the region on Drosophila polytene chromosomes that had been identified as the site of the choline acetyltransferase (Cha) gene by cytogenetic analysis. The cDNA insert consisted of a coding region 2190 nucleotides long, a 3'-noncoding region 284 nucleotides long, and EcoRI linkers. RNA analysis of Drosophila head poly(A)+ RNA with the cDNA insert as a probe showed the choline acetyltransferase mRNA to be approximately equal to 4700 nucleotides long.

Amino Acid Sequence↗

PubMed2026

Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D.

Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer-promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.

Cohesins↗

PubMed2003

Antitumor activity induced by regulatory RNA: possible role of RNA-dependent protein kinase and nuclear factor-kappaB.

Regulatory RNAs are noncoding RNAs that can regulate gene expression. Our previous results showed that regulatory RNAs can induce the production of interleukin-1, interleukin-2, interleukin-8, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, and Fas ligand (FasL). These cytokines and FasL are involved in host defense mechanisms against tumors. B16-F10 melanoma cells are highly metastatic to the lungs and we showed that lymphocytes treated with the regulatory B16-RNA reduce significantly the number of metastatic nodules. We also found that B16-RNA activates RNA-dependent protein kinase (PKR) and the active B16-RNA fraction is polyadenylated with a sedimentation coefficient of 18S. Our findings suggest that the antitumor activity of B16-RNA is mediated by PKR through activation of the transcription factor NF-kappaB. Thus, B16-RNA may act as a regulatory RNA and may regulate gene expression at transcriptional level. This study provides the rationale for the use of B16-RNA as an immunomodulator in melanoma.

Animals↗

PubMed1986

Processing of phage T4 td-encoded RNA is analogous to the eukaryotic group I splicing pathway.

Several features of the split td gene of phage T4 suggest an RNA processing mechanism analogous to that of the self-splicing rRNA of Tetrahymena and other group I eukaryotic introns. Previous work has revealed conserved sequence elements and the ability of td-encoded RNA to self-splice in vitro. We show here that a noncoded guanosine residue is covalently joined to the 5' end of the intron during processing. Further, we demonstrate the existence of linear and circular intron forms in RNA extracted from T4-infected cells and from uninfected Escherichia coli expressing the cloned td gene. Sequence analysis of the intron cyclization junction indicates that the noncoded guanosine and one additional nucleotide are lost from the 5' end of the intron upon cyclization. This analysis places a uridine residue upstream of the cyclization site, in analogy to three other group I cyclization junctions. These striking similarities to the splicing intermediates of eukaryotic group I introns point not only to an analogous processing pathway and conserved features of cyclization site recognition but also to a common ancestry between this prokaryotic intervening sequence and the group I eukaryotic introns.

Animals↗

PubMed1999

Transcriptional analysis of two endoinulinase genes inuA and inuB in Aspergillus niger and nucleotide sequences of their promoter regions.

Aspergillus niger 12 contained two copies of endoinulinase genes (inuA and inuB) in the genome (K. Ohta et al., Biosci. Biotechnol. Biochem., 62, 1731-1738, 1998). The inuA- and inuB-specific DNA probes were constructed according to the respective 3'-noncoding sequences that diverged from each other. Poly(A)+ RNA was prepared from mycelia grown on inulin, fructose, or glucose in submerged culture. Three endoinulinase cDNA sequences that corresponded to the coding regions and their 5'- and 3'-flanking regions were obtained by reverse transcription and subsequent polymerase chain reaction. Southern blot analysis revealed that the amplified cDNA 3'-noncoding sequences hybridized to the inuB probe but not to the inuA probe, regardless of the carbon source. The data suggest that only the inuB gene was transcribed constitutively. Four distinct 5' ends of the transcripts were observed at positions -80(A), -72(G), -69(A), and -65(A) from the start codon. The inuB mRNAs were polyadenylated at various sites between 94 and 297 bp downstream of the stop codon. We have determined the nucleotide sequences of the 1201- and 1017-bp 5'-noncoding regions of the inuA and inuB genes, respectively. The inuB promoter region included a putative TATA box at -116 (TATATA).

Journal Article↗

PubMed1986

The primary structure of chicken B-creatine kinase and evidence for heterogeneity of its mRNA.

cDNA clones for chicken B-CK were isolated by immunoscreening from a gizzard cDNA library constructed in the expression vector lambda gtll. The entire coding portion in addition to the complete 3' untranslated region and 42 bp of the 5' noncoding part are represented in the clone H4. On RNA blots H4 insert DNA hybridized to a 1600 bp poly(A)+ RNA from gizzard, brain and heart but not to breast or skeletal muscle RNA. In vitro generated sense strand transcripts of H4 insert DNA were translated in vitro into a protein indistinguishable from isolated, authentic B-CK. The distinct nucleotide sequences of H4 insert DNA and M-CK cDNA were translated into 82% homologous amino acid sequences. Sequence heterogeneity among the B-CK cDNA clones within both the 3' noncoding and even in the coding region indicates the existence of multiple B-CK mRNA species.

Amino Acid Sequence↗

PubMed1997

Engineering of homologous recombination hotspots with AU-rich sequences in brome mosaic virus.

Previously, we observed that crossovers sites of RNA recombinants clustered within or close to AU-rich regions during genetic recombination in brome mosaic bromovirus (BMV) (P. D. Nagy and J. J. Bujarski. J. Virol. 70:415-426, 1996). To test whether AU-rich sequences can facilitate homologous recombination, AU-rich sequences were introduced into parental BMV RNAs (RNA2 and RNA3). These insertions created a homologous RNA2-RNA3 recombination hotspot. Two other AU-rich sequences also supported high-frequency homologous recombination if a common sequence with high or average G/C content was present immediately upstream of the AU-rich element. Homologous RNA recombination did not require any additional sequence motifs or RNA structures and was position nonspecific within the 3' noncoding region. These results suggest that nucleotide content (i.e., the presence of common 5' GC-rich or moderately AU-rich and 3' AU-rich regions) is the important factor that determines the sites of homologous recombination. A mechanism that involves replicase switching during synthesis of positive-sense RNA strands is presented to explain the observed results.

Base Sequence↗

PubMed1994

Increase in the relative fitness of a plant virus RNA associated with its recombinant nature.

A recombination event at the 3' end of RNA 3 in a pseudorecombinant virus (C1C2T3) having RNAs 1 and 2 from TrK7-cucumber mosaic virus (CMV) and RNA 3 from P-tomato aspermy virus (TAV) was detected by ribonuclease protection assay (RPA). Sequence analysis of the 3' end of RNA 3 of C1C2T3 and of its parental CMV and TAV strains showed that RNA 3 of C1C2T3 had a hybrid nature in which most of the 3' noncoding region (3' ncr), including the whole 3' terminal tRNA-like structure, was derived from CMV RNA 2 by recombination. Recombination may have occurred in two steps. The first one would have caused the duplication of a large region 5' to the 3' end tRNA-like structure, derived from TAV and from CMV. The second one would have eliminated the TAV-derived sequences in this duplicated region. Competition experiments in tobacco plants showed that in a context of RNA 1 + 2 from CMV, RNA 3 from TAV is outcompleted by RNA 3 of CMV, but the recombinant TAV RNA 3 with the 3' end of CMV outcompetes both TAV and CMV RNA 3. This shows an increase in relative fitness associated with the recombinant nature of RNA 3. Our results document the potential importance of RNA-RNA recombination in the determination of the genetic structure of RNA viral populations.

Base Sequence↗

PubMed1990

Transcriptional and Post-Transcriptional Regulation of RNA Levels in Maize Mitochondria.

Relatively little is known about the mechanisms that govern the expression of plant mitochondrial genomes. We have addressed this problem by analyzing the transcriptional activity of different regions of the maize mitochondrial genome using both in vivo and isolated mitochondrial pulse-labeling systems. The regions examined included the protein genes atpA, atp6, and coxII, the 26S, 18S, and 5S rRNA genes, and sequences surrounding the rRNA genes. The rRNAs were found to be transcribed at rates fivefold to 10-fold higher than the protein genes. These rate differences are comparable with the differences in abundance of these species in the total or steady-state RNA population. Pulse-labeled RNA unexpectedly detected transcription of all regions examined, including approximately 21 kilobases of presumed noncoding sequences flanking the rRNA genes for which stable transcripts were not detected. The results obtained with RNA labeled for short pulses in vivo and in isolated mitochondria were similar, suggesting that isolated mitochondria provide a faithful run-on transcription assay. Our results indicate that the absence in total RNA of transcripts homologous to a given region of maize mitochondrial DNA does not necessarily exclude transcriptional activity of that region and that both transcriptional and post-transcriptional processes play important roles in maize mitochondrial genome expression.

Journal Article↗

PubMed1997

A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase.

Editing of RNA changes the read-out of information from DNA by altering the nucleotide sequence of a transcript. One type of RNA editing found in all metazoans uses double-stranded RNA (dsRNA) as a substrate and results in the deamination of adenosine to give inosine, which is translated as guanosine. Editing thus allows variant proteins to be produced from a single pre-mRNA. A mechanism by which dsRNA substrates form is through pairing of intronic and exonic sequences before the removal of noncoding sequences by splicing. Here we report that the RNA editing enzyme, human dsRNA adenosine deaminase (DRADA1, or ADAR1) contains a domain (Zalpha) that binds specifically to the left-handed Z-DNA conformation with high affinity (KD = 4 nM). As formation of Z-DNA in vivo occurs 5' to, or behind, a moving RNA polymerase during transcription, recognition of Z-DNA by DRADA1 provides a plausible mechanism by which DRADA1 can be targeted to a nascent RNA so that editing occurs before splicing. Analysis of sequences related to Zalpha has allowed identification of motifs common to this class of nucleic acid binding domain.

Adenosine Deaminase↗

PubMed2006

Structural and biochemical basis for misfolded RNA recognition by the Ro autoantigen.

The Ro autoantigen is ring-shaped, binds misfolded noncoding RNAs and is proposed to function in quality control. Here we determine how Ro interacts with misfolded RNAs. Binding of Ro to misfolded precursor (pre)-5S ribosomal RNA requires a single-stranded 3' end and helical elements. As mutating most sequences of the helices and tail results in modest decreases in binding, Ro may be able to associate with a range of RNAs. Ro binds several other RNAs that contain single-stranded tails. A crystal structure of Ro bound to a misfolded pre-5S rRNA fragment reveals that the tail inserts into the cavity, while a helix binds on the surface. Most contacts of Ro with the helix are to the backbone. Mutagenesis reveals that Ro has an extensive RNA-binding surface. We propose that Ro uses this surface to scavenge RNAs that fail to bind their specific RNA-binding proteins.

Animals↗

PubMed1977

Complete nucleotide sequence of the 5' noncoding region of rabbit beta-globin mRNA.

The 5' noncoding region sequence of rabbit beta-globin mRNA has been determined. This region is 53 nucleotides long, not including the A-U-G initiator sequence or m7Gppp "cap" structure. 32P-labeled DNA complementary to the 5' noncoding region was synthesized using reverse transcriptase with the synthetic deoxyoctanucleotide d(G-C-A-C-C-A-T-T) as a "primer". The cDNA produced was then sequenced using a modification of the gel-sequencing technique previously developed for DNA sequencing (G.G. Brownlee and E.M. Cartwright, manuscript in preparation). The sequence obtained was checked by depurination and nearest-neighbor analysis. The known sequence at the 3' end of rabbit 18S ribosomal RNA cannot base-pair extensively with the 5' noncoding region of beta-globin mRNA; however, it does form 6 base pairs around the initiation codon.

Animals↗

PubMed1992

Mutagenesis of a hexanucleotide sequence conserved in potexvirus RNAs.

Biologically active in vitro transcripts were synthesized from a cloned cDNA of a defective RNA (D RNA) of clover yellow mosaic virus (CYMV) and were used to determine if a hexanucleotide motif (5'-ACUUAA) conserved in the 3' noncoding region of potexvirus RNAs is essential for accumulation of progeny D RNA in planta. Deletion of rearrangement of the entire hexanucleotide sequence in the D RNA resulted in no detectable accumulation of progeny D RNA when coinoculated with helper CYMV RNA. Single-base substitutions of the four central nucleotides of the hexanucleotide sequence revealed that viable D RNAs can tolerate single residue changes at positions 3 and 5 only. These results suggest that the hexamer motif is involved in the process of D RNA propagation. The hexanucleotide sequence was also identified in the negative strand of potexvirus RNAs in the regions proposed to represent subgenomic RNA (sgRNA) promoters. In addition, the hexamer motif is present in similar regions in carlavirus RNAs. The conservation of this hexanucleotide (in orientation and position) in potexvirus and carlavirus RNAs, which serve as templates for full-length negative-strand synthesis and sgRNA production, strongly suggests that it plays a functional role in the synthesis of viral RNAs. Taken together, our data support our previous proposal (Bancroft et al., 1991. J. Gen. Virol. 72, 2173-2181) that the hexanucleotide sequence acts as a cis element involved in synthesis of full-length negative-sense viral RNA and further implicate the sequence in a similar role in production of positive-sense sgRNA.

Capsid↗

PubMed1997

GB virus C/hepatitis G virus infection among Korean patients with liver diseases and general population.

GB virus C and hepatitis G virus (GBV-C/HGV) have been identified from the patients with acute or chronic liver diseases as possible agents of non-B, non-C hepatitis by two different groups, independently. To investigate whether GBV-C/HGV plays a role among Korean patients with liver diseases, GBV-C/HGV RNA were evaluated in 337 sera by the reverse transcription polymerase chain reaction (RT-PCR) using specific primers derived from 5'-noncoding region of GBV-C/HGV genome. GBV-C/HGV RNA was identified in 11/337 (3.3%). They consisted of 1/160 (0.6%) and 10/177 (3.3%) among the general population and patients with liver diseases, respectively (P < 0.01). Nucleotide sequences of all PCR amplicons were determined by the dideoxy chain termination method and analyzed by molecular evolutionary methods. The phylogenetic tree showed all sequences could be divided into three genotypes. These results indicate that: (1) GBV-C/HGV already exist in Korea; (2) GBV-C/HGV may play some role as an etiologic factor among the Korean patients with liver diseases; (3) GBV-C/HGV infection is rare among Korean general population; and (4) there are at least three different types of GBV-C/HGV in Korea.

Adolescent↗

PubMed2026

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗