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Results for “noncoding RNA”

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PubMed2006

Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies.

OBJECTIVE: Peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) have increased expression of genes typically induced by type I interferon (IFN). However, it has been difficult to identify and quantify the factors responsible for activation of the IFN pathway in SLE. To characterize these mediators, we developed an assay that measures the functional effects of plasma or serum components on the gene expression of cultured target cells. METHODS: WISH epithelial cell line cells were cultured with medium, with recombinant IFNalpha, IFNbeta, or IFNgamma, or with 50% plasma from SLE patients (n = 73), rheumatoid arthritis (RA) patients (n = 19), or healthy donors (n = 30). Real-time quantitative polymerase chain reaction was used to determine WISH cell expression of IFN target genes, including PRKR, IFIT1, IFI44, MX1, and C1orf29 (preferentially induced by IFNalpha) and CXCL9 (Mig) (preferentially induced by IFNgamma). RESULTS: IFNalpha-regulated genes were induced by SLE plasma samples, but not by most of the RA or healthy control plasma samples. The activity in SLE plasma was inhibited >90% by anti-IFNalpha antibody, but not by anti-IFNbeta or anti-IFNgamma antibodies. The expression of each IFNalpha target gene induced by SLE plasma correlated with the expression of that gene studied ex vivo in PBMCs from the same patients and with the titer of anti-RNA binding protein (anti-RBP)-specific autoantibodies. Plasma activity paralleled PBMC expression of IFNalpha-inducible genes over time. CONCLUSION: IFNalpha in SLE plasma is a major stimulus of IFN target gene expression and is related to expression of those genes in PBMCs from SLE patients and to the titer of anti-RBP autoantibodies. These data provide additional support for the view that IFNalpha mediates immune system activation and dysregulation in SLE.

Antibodies↗

PubMed1993

Promoter, spliced leader, and coding sequence for BICP4, the largest of the immediate-early proteins of bovine herpesvirus 1.

We report the complete nucleotide sequence of the bovine herpesvirus 1 (BHV-1) immediate-early gene encoding BICP4, the homolog of the ICP4 protein of herpes simplex virus. Combined with previous mapping studies, the sequence analysis revealed that the transcript for BICP4 consisted of a noncoding leader RNA (exon 1; 0.35 kb) separated by an intron (0.46 kb) from the main body (exon 2; 4.1 kb). The open reading frame for BICP4 (1343 amino acid residues) started 27 nt after the splice site and extended across exon 2 for most of its length, BICP4 contained two domains of high homology (regions 2 and 4), which had been recognized earlier to be most conserved in the ICP4 homologs of alpha-herpesviruses and to be functionally important. These domains were flanked by three regions of lower but still discernible homology. Unique features of BICP4 were two large clusters of glutamic acid residues near the end of region 3, and the displacement of a polyserine tract to region 5, which in all other ICP4 homologs residues near the end of region 1. Transient expression assays showed that BICP4 repressed its own promoter and activated other herpes-virus genes. The 8.1-kb sequence summarized here completes analysis of the inverted repeats of the BHV-1 genome; it includes a segment (2.5 kb) upstream of the BICP4 gene apparently devoid of coding sequences but containing numerous scattered transcription signals.

Alphaherpesvirinae↗

PubMed2006

Ferritins: iron/oxygen biominerals in protein nanocages.

Ferritin protein nanocages that form iron oxy biominerals in the central nanometer cavity are nature's answer to managing iron and oxygen; gene deletions are lethal in mammals and render bacteria more vulnerable to host release of antipathogen oxidants. The multifunctional, multisubunit proteins couple iron with oxygen (maxi-ferritins) or hydrogen peroxide (mini-ferritins) at catalytic sites that are related to di-iron sites oxidases, ribonucleotide reductase, methane monooxygenase and fatty acid desaturases, and synthesize mineral precursors. Gated pores, distributed symmetrically around the ferritin cages, control removal of iron by reductants and chelators. Gene regulation of ferritin, long known to depend on iron and, in animals, on a noncoding messenger RNA (mRNA) structure linked in a combinatorial array to functionally related mRNA of iron transport, has recently been shown to be linked to an array of proteins for antioxidant responses such as thioredoxin and quinone reductases. Ferritin DNA responds more to oxygen signals, and ferritin mRNA responds more to iron signals. Ferritin genes (DNA and RNA) and protein function at the intersection of iron and oxygen chemistry in biology.

Catalysis↗

PubMed1986

Foscarnet decreases serum and liver duck hepatitis B virus DNA in chronically infected ducks.

Foscarnet (trisodium phosphonoformate) is a new antiviral compound with in vitro inhibitory effects against the DNA polymerases of hepadna viruses. To study the effects of the drug in chronic hepadna virus infection, we treated ducks chronically infected with duck hepatitis B virus for 10 days with either low-dose foscarnet (50 mg/kg i.p. b.i.d.), high-dose foscarnet (250 mg/kg i.p. b.i.d.), or sterile water injections. Serum duck hepatitis B virus DNA and intrahepatic replicative forms of the virus were measured using molecular biological techniques with both a double-stranded radiolabeled DNA probe and a plus-strand (noncoding) specific RNA probe. We found a dose-related decrease in serum and intrahepatic duck hepatitis B virus DNA during treatment, with a rapid return toward baseline values after the cessation of treatment. There was a disproportionate decrease in the plus strand of viral DNA with treatment. We conclude that foscarnet exerts its effect in hepadna virus infection through inhibition of viral DNA polymerase. Further study is necessary to determine whether foscarnet, by itself or in combination with other treatment modalities, has a role to play in the treatment of chronic hepatitis B infections in humans.

Animals↗

PubMed1986

Poliovirus temperature-sensitive mutant containing a single nucleotide deletion in the 5'-noncoding region of the viral RNA.

The effect on viral replication of deleting nucleotide 10 of the poliovirus RNA genome was determined. This deletion, which removes a base pair from a predicted hairpin structure in the viral RNA, was introduced into full-length cDNA. Virus recovered after transfection of HeLa cells with the mutated cDNA contained the expected deletion and was temperature sensitive for plaque formation. Analysis of viral replication by one-step growth experiments indicated that mutant virus production at the nonpermissive temperature was at least 100 times less than that of wild type virus, and release of virus from mutant-infected cells was delayed. The synthesis of positive- and negative-strand viral RNA in mutant virus-infected cells was temperature sensitive. Virus-specific protein synthesis in mutant virus-infected cells was not temperature sensitive but occurred at a slower rate than that of wild type virus at permissive and nonpermissive temperatures. Replication of the mutant virus was sensitive to actinomycin D, in contrast to the wild type parent virus, which was resistant to the drug. Mutant virus stocks contained a small percentage of ts+ viruses that were able to form plaques at the nonpermissive temperature. Nucleotide sequence analysis of genomic RNA from these ts+ viruses revealed a single base change at position 34 from a G to U. In the positive RNA strand, the effect of this mutation is to restore to the hairpin structure the single base pair whose formation was prevented by the original deletion. The ts+ pseudorevertants replicated to similar titers as wild type virus at 33 and 38.5 degrees and were partially sensitive to actinomycin D.

Base Sequence↗

PubMed2026

ceRNA network of lncRNAs and mRNAs in OSF-to-OSCC progression: Diagnostic biomarkers and functional pathways.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic potentially malignant disorder that can progress to oral squamous cell carcinoma (OSCC). Although dysregulated non-coding RNAs have been implicated in oral carcinogenesis, the competing endogenous RNA (ceRNA)-mediated regulatory mechanisms underlying OSF-to-OSCC progression remain poorly understood. This study aimed to identify candidate regulatory molecules and construct a putative lncRNA-miRNA-mRNA network associated with malignant transformation. METHODS: Publicly available microarray datasets (GSE117973 and GSE125866) were analyzed to identify differentially expressed genes between OSF and OSCC. Differentially expressed transcripts were classified into mRNAs and lncRNAs based on public transcript annotations. Highly correlated lncRNA-mRNA pairs were identified using Pearson correlation analysis and integrated with multiMiR-supported miRNA-mRNA interactions obtained from public databases to construct a putative ceRNA regulatory network. Functional characterization focused on apoptosis, epithelial-mesenchymal transition (EMT), and immune checkpoint-related pathways. Receiver operating characteristic (ROC) analysis was performed to evaluate diagnostic performance, and selected biomarkers were externally validated using The Cancer Genome Atlas (TCGA) OSCC cohort. RESULTS: Integrated transcriptomic analysis identified several dysregulated mRNAs and lncRNAs associated with OSF-to-OSCC progression. Network analysis highlighted TBC1D3B, RREB1, TEAD3, SREBF1, TMEM41B, FOXK2, and KIAA1958 as prominent hub genes within the putative regulatory network. Functional analyses demonstrated significant associations with apoptosis-, EMT-, and immune checkpoint-related genes, suggesting potential involvement in multiple biological processes contributing to malignant transformation. Several hub genes exhibited strong diagnostic performance, with ROC analysis yielding AUC values ranging from 0.891 to 1.000, indicating excellent discrimination between OSF and OSCC samples. External validation using TCGA further supported the relevance of the identified biomarkers in OSCC. CONCLUSIONS: This study provides a comprehensive transcriptomic framework describing putative lncRNA-miRNA-mRNA regulatory interactions associated with OSF progression to OSCC. The identified hub genes and regulatory networks represent candidate biomarkers for early detection and provide a foundation for future mechanistic and experimental validation. As the proposed ceRNA interactions are computationally inferred, further biological validation is required before clinical application.

RNA, Long Noncoding↗

PubMed2004

Path to equality strewn with roX.

Male flies hypertranscribe most genes along their single X chromosome to match the output of females with two X chromosomes. This is mediated by chromatin modifications carried out by the MSL complex composed of noncoding roX RNA and at least five MSL proteins. New results indicate that one of these subunits, the MOF acetyltransferase, not only acts on histone H4, but on itself and MSL3. Cycles of covalent modifications of the MSL subunits may determine the proper level of hypertranscription or control cis spreading along the chromosome. The MSL complex binds to the roX genes, the very source of the RNA component of the complex. New details of how this interaction occurs hint at a possible autoregulatory function. Finally, despite intensive efforts, the molecular mechanism by which the MSL complex distinguishes the X from the autosomes remains a mystery. The MSL complex is able to spread epigenetically from the site of roX transcription, and recent work has defined the conditions that control local cis spreading. However, it is equally clear that soluble MSL complex can distinguish the X chromosome from autosomes. Reconciling all these findings into a unified model presents a challenge.

Animals↗

PubMed2002

Cloning of the mRNA of overexpression in colon carcinoma-1: a sequence overexpressed in a subset of colon carcinomas.

We have identified a novel human cDNA overexpressed in a colon carcinoma cell line, TC7, established from a tumor with a normal karyotype arising in a patient with a hereditary nonpolyposis colorectal carcinoma. The OCC-1 (overexpressed in colon carcinoma-1) gene is composed of six exons and located in the q24.1 region of chromosome 12. It is transcribed as two mRNA species that differ in their 5'- and 3'-terminal ends. Abundant accumulation of both transcripts was found in placenta, skeletal muscle, kidney, and pancreas tissues. Absent or very faint expression was observed in heart, brain, lung and liver tissues. Overexpressed in colon carcinoma-1 cDNA direct in vitro translation of several polypeptides whose size is shorter than 9 kDa. Attempts to produce antibodies against these synthesized polypeptides in Escherichia coli failed. The absence of sequences at the mRNA and DNA levels hybridizing with mouse sequences together with the absence of a large open reading frame raise the possibility that OCC-1 sequences appeared recently in evolution and are transcribed as two noncoding regulatory RNA. Elevated levels of OCC-1 mRNA were observed in three of eight colon carcinomas as compared to normal mucosa of the same patient. Since these tumors shared the same characteristics of having a near diploid karyotype, OCC-1 overexpression may be a hallmark of this subset of colon carcinomas.

Adult↗

PubMed2004

Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation.

Imprinted genes are expressed from only one of the parental chromosomes and are marked epigenetically by DNA methylation and histone modifications. The imprinting center 2 (IC2) on mouse distal chromosome 7 is flanked by several paternally repressed genes, with the more distant ones imprinted exclusively in the placenta. We found that most of these genes lack parent-specific DNA methylation, and genetic ablation of methylation does not lead to loss of their imprinting in the trophoblast (placenta). The silent paternal alleles of the genes are marked in the trophoblast by repressive histone modifications (dimethylation at Lys9 of histone H3 and trimethylation at Lys27 of histone H3), which are disrupted when IC2 is deleted, leading to reactivation of the paternal alleles. Thus, repressive histone methylation is recruited by IC2 (potentially through a noncoding antisense RNA) to the paternal chromosome in a region of at least 700 kb and maintains imprinting in this cluster in the placenta, independently of DNA methylation. We propose that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications, and that this mechanism was subsequently made more stable for use in embryonic lineages by the recruitment of DNA methylation.

Animals↗

PubMed2004

Functional integration of the histone acetyltransferase MOF into the dosage compensation complex.

Dosage compensation in flies involves doubling the transcription of genes on the single male X chromosome to match the combined expression level of the two female X chromosomes. Crucial for this activation is the acetylation of histone H4 by the histone acetyltransferase (HAT) MOF. In male cells, MOF resides in a complex (dosage compensation complex, DCC) with MSL proteins and noncoding roX RNA. Previous studies suggested that MOF's localization to the X chromosome was largely RNA-mediated. We now found that contact of the MOF chromo-related domain with roX RNA plays only a minor role in correct targeting to the X chromosome in vivo. Instead, a strong, direct interaction between a conserved MSL1 domain and a zinc finger within MOF's HAT domain is crucial. The functional consequences of this interaction were studied in vitro. Simultaneous contact of MOF with MSL1 and MSL3 led to its recruitment to chromatin, a dramatic stimulation of HAT activity and to improved substrate specificity. Activation of MOF's HAT activity upon integration into the DCC may serve to restrict the critical histone modification to the male X chromosome.

Acetylation↗

PubMed2001

Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes.

Imprinting of the maternally-expressed Igf2r gene is controlled by an intronic imprint control element (ICE) known as Region2 that contains the promoter of the noncoding Air RNA, whose transcript overlaps the silenced paternal Igf2r promoter in an antisense orientation. Two novel imprinted genes, Slc22a2 and Slc22a3 are described here that lie 110 and 155 kb 3' to Igf2r and that are not overlapped by the Air transcript but are regulated by the Igf2r-ICE, as previously shown for Igf2r. These results identify a new cluster of imprinted genes whose repression by the bidirectional action of the Region2-ICE is independent of transcript overlap by the Air RNA.

Animals↗

PubMed1979

Comparison of total sequence of a cloned rabbit beta-globin gene and its flanking regions with a homologous mouse sequence.

The nucleotide sequence of a cloned rabbit chromosomal DNA segment of 1620 nucleotides length which contains a beta-globin gene is presented. The coding regions are separated into three blocks by two intervening sequences of 126 and 573 base pairs, respectively. The rabbit sequence was compared with a homologous mouse sequence. The segments flanking the rabbit gene, as well as the coding regions, the 5' noncoding and part of the 3' noncoding messenger RNA sequences are similar to those of the mouse gene; the homologous introns, despite identical location, are distinctly dissimilar except for the junction regions. Homologous introns may be derived from common ancestral introns by large insertions and deletions rather than be multiple point mutations.

Animals↗

PubMed2005

Cloning and identification of a microRNA cluster within the latency-associated region of Kaposi's sarcoma-associated herpesvirus.

MicroRNAs (miRNAs) are small, noncoding regulatory RNA molecules that bind to 3' untranslated regions (UTRs) of mRNAs to either prevent their translation or induce their degradation. Previously identified in a variety of organisms ranging from plants to mammals, miRNAs are also now known to be produced by viruses. The human gammaherpesvirus Epstein-Barr virus has been shown to encode miRNAs, which potentially regulate both viral and cellular genes. To determine whether Kaposi's sarcoma-associated herpesvirus (KSHV) encodes miRNAs, we cloned small RNAs from KSHV-positive primary effusion lymphoma-derived cells and endothelial cells. Sequence analysis revealed 11 isolated RNAs of 19 to 23 bases in length that perfectly align with KSHV. Surprisingly, all candidate miRNAs mapped to a single genomic locale within the latency-associated region of KSHV. These data suggest that viral and host cellular gene expression may be regulated by miRNAs during both latent and lytic KSHV replication.

Cloning, Molecular↗

PubMed2001

Investigation of elements sufficient to imprint the mouse Air promoter.

Imprinted maternal-allele-specific expression of the mouse insulin-like growth-factor type 2 receptor (Igf2r) gene depends on a 3.7-kb element named region 2, located in the second intron of the gene. Region 2 carries a maternal-allele-specific methylation imprint and contains an imprinted CpG island promoter (Air) that expresses a noncoding antisense RNA from the paternal inherited allele only. Here, we use transgenes to test the minimal requirements for imprinting of Air and to test if the action of region 2 is restricted to Igf2r. Transgenes up to 9 kb with Air as a single promoter are expressed but not imprinted. When coupled to the Igf2r CpG island promoter on a 44-kb transgene, Air was imprinted in one of three lines. However, Air on a 4.6-kb fragment is also imprinted in 2 of 14 lines when inserted in an intron of an adenine phosphoribosyltransferase (Aprt) transgene, and in one line, the imprinted methylation and expression of Air have been transferred onto the Aprt CpG island promoter. These data suggest that a dual CpG island promoter setting may facilitate Air imprinting as a short transgene and also show that Air can transfer imprinting onto other genes. However, for reliable Air imprinting, elements are necessary that are located outside a 44-kb region spanning the Air-Igf2r promoters.

Adenine Phosphoribosyltransferase↗

PubMed2005

The MRG domain mediates the functional integration of MSL3 into the dosage compensation complex.

The male-specific-lethal (MSL) proteins in Drosophila melanogaster serve to adjust gene expression levels in male flies containing a single X chromosome to equal those in females with a double dose of X-linked genes. Together with noncoding roX RNA, MSL proteins form the "dosage compensation complex" (DCC), which interacts selectively with the X chromosome to restrict the transcription-activating histone H4 acetyltransferase MOF (males-absent-on-the-first) to that chromosome. We showed previously that MSL3 is essential for the activation of MOF's nucleosomal histone acetyltransferase activity within an MSL1-MOF complex. By characterizing the MSL3 domain structure and its associated functions, we now found that the nucleic acid binding determinants reside in the N terminus of MSL3, well separable from the C-terminal MRG signatures that form an integrated domain required for MSL1 interaction. Interaction with MSL1 mediates the activation of MOF in vitro and the targeting of MSL3 to the X-chromosomal territory in vivo. An N-terminal truncation that lacks the chromo-related domain and all nucleic acid binding activity is able to trigger de novo assembly of the DCC and establishment of an acetylated X-chromosome territory.

Acetyltransferases↗

PubMed2005

A systematic search for new mammalian noncoding RNAs indicates little conserved intergenic transcription.

BACKGROUND: Systematic identification and functional characterization of novel types of noncoding (nc)RNA in genomes is more difficult than it is for protein coding mRNAs, since ncRNAs typically do not possess sequence features such as splicing or translation signals, or long open reading frames. Recent "tiling" microarray studies have reported that a surprisingly larger proportion of mammalian genomes is transcribed than was previously anticipated. However, these non-genic transcripts often appear to be low in abundance, and their functional significance is not known. RESULTS: To systematically search for functional ncRNAs, we designed microarrays to detect 3,478 intergenic and intronic sequences that are conserved between the human, mouse, and rat genomes, and that score highly by other criteria that characterize ncRNAs. We probed these arrays with total RNA isolated from 16 wild-type mouse tissues. Among 55 candidates for highly-expressed novel ncRNAs tested by northern blotting, eight were confirmed as small, highly-and ubiquitously-expressed RNAs in mouse. Of the eight, five were also detected in rat tissues, but none were detected at appreciable levels in human tissues or cultured cells. CONCLUSION: Since the sequence and expression of most known coding transcripts and functional ncRNAs is conserved between human and mouse, the lack of northern-detectable expression in human cells and tissues of the novel mouse and rat ncRNAs that we identified suggests that they are not functional or possibly have rodent-specific functions. Our results confirm that relatively little of the intergenic sequence conserved between human, mouse and rat is transcribed at high levels in mammalian tissues, possibly suggesting a limited role for transcribed intergenic and intronic sequences as independent functional elements.

Animals↗

PubMed2026

A Comparative Analysis of the Methylation Status of Non-Coding RNA Promoters in Fibroid and Matched Myometrium.

Uterine fibroids exhibit dysregulated expression of non-coding RNAs (ncRNAs), although the underlying mechanisms remain incompletely understood. We investigated promoter DNA methylation and its relationship with ncRNA expression in fibroids. Genomic DNA from eight paired fibroid and matched myometrial tissues was analyzed using MeDIP-chip to identify differentially methylated ncRNA promoters. Selected candidates were validated by methylation-specific PCR (MSP) in 16 paired samples, and transcript expression was assessed by qRT-PCR in 68-94 paired specimens. MeDIP-chip identified 538 lncRNAs and 61 miRNAs with differential promoter methylation, including 300 hypermethylated and 238 hypomethylated lncRNAs and 47 hypermethylated and 14 hypomethylated miRNAs. Promoter methylation was not significantly correlated with transcript expression (r = -0.1224). MSP confirmed hypermethylation of LINC-PINT and MIR9-3 and hypomethylation of WT1-AS and TTLL10-AS1. Correspondingly, LINC-PINT and MIR9-3 expression was decreased, whereas WT1-AS and TTLL10-AS1 expression was increased in fibroids. However, LINC-PINT and TTLL10-AS1 methylation did not fully correspond with MeDIP-chip findings. These results reveal widespread ncRNA promoter methylation alterations in uterine fibroids but demonstrate that genome-wide methylation does not consistently predict transcript expression, highlighting the complexity of ncRNA epigenetic regulation and the importance of locus-specific validation.

Humans↗

PubMed2006

MicroRNA trafficking and human cancer.

MicroRNAs (miRNAs) are short endogenous noncoding small RNA molecules with 21 to 25 nucleotides (nt) in length, which negatively regulate gene expression either by degrading specific mRNA or impeding translation at the transcriptional and post-transcriptional level. Recent advances suggest that miRNAs play prominent roles in development, genome organization, viral and transposon defense, and human disease, including neurodegenerative and metabolic diseases. Surprisingly, miRNAs are now linked with a variety of cancers, in which a reduced expression or overexpression may lead to oncogene or tumor suppressor gene-like actions. Here we will overview the miRNA pathway and its regulation with emphasis on the links with human cancer. Finally potential applications of miRNA in tumor diagnosis and therapy will be discussed.

Gene Expression Regulation, Neoplastic↗