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PubMed2004

Cloning and sequencing of a cDNA encoding for a protein specifically expressed in human testis, ovary and placenta.

Reproductive cell/tissue-specific antigens are attractive candidates for the development of a contraceptive vaccine. Using the differential display technology, a human cDNA fragment of 322-bp, designated as T17, was identified showing specific expression in the human testis. The T17 cDNA fragment was used as a probe to screen the human testis cDNA-lambda gt10 library. After screening, one positive clone of approximately 1.1 kb having T17 nucleotide (nt) sequence was obtained. The 5' and 3' termini of this cDNA clone were extended by using 5' and 3' RACE procedures that yielded a full-length cDNA, designated as the TOP gene. The TOP cDNA is 1,480-bp long and has an ORF of 463 aa with the first ATG Met start codon at nucleotide (nt) 64 and the stop codon TGA at nt 1452. The translated protein has a calculated molecular mass of 49.3 kD with isoelectric point of 12.17. The deduced amino acid (aa) has one potential N-glycosylation site, and several phosphorylation and myristoylation sites. Hydropathy plot generated from the deduced aa sequence showed it to be a surface protein. Comprehensive computer search in the database did not reveal any homology to any existing sequences both at the nt and aa levels. The TOP cDNA was found to be completely localized on the human chromosome 16 at the nt position 507833-506354, with the TOP ORF at the nt position 507770-506354. Northern blot analysis using three human Northern blots, indicated the specific expression of TOP gene in the human testis, ovary and placenta. RT-PCR-Southern blot analysis also confirmed tissue-specific expression of the TOP gene. The TOP cDNA may help us to gain insight into transcriptional control of the differentially expressed reproductive tissue-specific genes. It may also find clinical applications in the development of a contraceptive vaccine, and specific diagnosis and treatment of infertility in humans.

Blotting, Northern↗

PubMed2026

Oxidative Stress Associated LncRNAs as Potential Biomarkers for Prognosis and Immune Responses in Lung Squamous Cell Carcinoma Patients.

Long-chain non-coding RNA (lncRNA) significantly influences lung squamous cell carcinoma's (LUSC) prognostic value and immune infiltration. This study aimed to demonstrate how oxidative stress-related lncRNAs impact lung squamous cell carcinoma (SCC). The Cancer Genome Atlas (TCGA) dataset gathered transcriptome information and related clinical data for LUSC. To build a prognostic model, 10 prognostic-related genes were identified using a series of bioinformatics analyses that compared the OS gene's aberrant expression in tumor and healthy tissues, as well as its association with malignancy. Subjects were stratified into high- and low-risk groups based on the median risk score derived from the 10-gene signature. While the mathematical risk model demonstrated limited independent predictive performance in the validation cohort (AUC ~ 0.5), functional and immunological evaluations revealed significant differences in the tumor microenvironment (TME) across risk strata. Specifically, high-risk patients exhibited distinct immune infiltration profiles and altered immunological scores relative to their low-risk counterparts. Therefore, rather than serving as a direct clinical prediction tool, this oxidative stress-related lncRNA signature provides valuable biological insights into the immune landscape of LUSC and highlights potential therapeutic targets for further mechanistic investigation.

Humans↗

PubMed2026

LINC01871-Mediated Sensitivity to Cyclin-Dependent Kinase 4/6 Inhibitors in Human Breast Cancer.

Breast cancer remains the most frequently diagnosed malignancy in women, and resistance to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors limits long-term treatment efficacy. This study aimed to identify long non-coding RNAs (lncRNAs) associated with predicted sensitivity to CDK4/6 inhibitors and to investigate their biological functions in breast cancer. Transcriptomic data from The Cancer Genome Atlas (TCGA) and drug sensitivity data from the Genomics of Drug Sensitivity in Cancer 2 (GDSC2) database were integrated, and drug sensitivity was predicted using the oncoPredict algorithm. Candidate lncRNAs were identified through differential expression analysis, weighted gene co-expression network analysis, prognostic analysis, and machine learning. The biological functions of LINC01871 were subsequently evaluated using in vitro and in vivo experiments. Sixty-two lncRNAs associated with predicted sensitivity to ribociclib and palbociclib were identified, and six core lncRNAs were selected. LINC01871 showed the highest discriminatory performance for predicted drug sensitivity. Overexpression of LINC01871 was associated with increased sensitivity of breast cancer cells to ribociclib and palbociclib, inhibition of cell proliferation, promotion of apoptosis, and suppression of nuclear factor kappa B (NF-κB) signaling. Single-cell transcriptomic analysis demonstrated high LINC01871 expression in T cells and natural killer (NK) cells, while transcriptome-based immune infiltration analyses showed that high LINC01871 expression was associated with increased immune infiltration. These findings identify LINC01871 as a candidate biomarker of sensitivity to CDK4/6 inhibitors and demonstrate its tumor-suppressive effects in breast cancer. Further clinical and mechanistic studies are required to validate its predictive value and therapeutic relevance.

Humans↗

PubMed2026

LncRNA RP11-708J19.2 promotes colorectal cancer progression by binding to SIRT7 via regulating H3K18ac.

Colorectal cancer (CRC) is a prevalent malignancy with a complex genetic basis. Recent genome-wide association studies (GWAS) have identified a susceptibility locus at 3p21.31, however, the functional SNP(s) underlying the association between the 3p21.31 region and CRC remain to be elucidated. In this study, we identified rs2101247 as the potential functional SNP and further demonstrated that rs2101247 is significantly associated with the expression of the nearby long non-coding RNA (lncRNA) RP11-708J19.2 (ENSG00000271161.1). Functional experiments showed that RP11-708J19.2 is upregulated in CRC tumor tissues, and its knockdown reduces cell viability while promoting apoptosis in SW1116 and HCT116 cell lines. Mechanistically, RP11-708J19.2 interacts directly with the deacetylase SIRT7, modulating histone H3K18 acetylation (H3K18ac). Specifically, RP11-708J19.2 knockdown leads to a significant upregulation of H3K18ac levels, implicating a SIRT7-mediated epigenetic pathway in CRC progression. Our findings elucidate a novel functional SNP-lncRNA axis that contributes to CRC pathogenesis, providing potential biomarkers for early detection and therapeutic targets for intervention.

Humans↗

PubMed2006

Hashimoto's encephalopathy and motor neuron disease: a common autoimmune pathogenesis?

Hashimoto's encephalopathy is a rare complication of autoimmune thyroiditis not associated with thyroidal function decline. We report a 50-year-old man presenting with lower motor neuron symptoms evolving over 3 years and changes in behavior associated with attentive and cognitive impairment occurring in the last few months. Memory deficits, emotional instability, marked dysarthria, mild symmetric weakness of the lower extremities and fasciculations were the most striking clinical features. EEG was diffusely slow, cranial MRI revealed multiple subcortical white matter lesions, CSF protein was slightly elevated, electromyographic recordings showed acute and chronic denervation and extremely high TPO antibody titers were found in the serum. Hashimoto's encephalopathy and lower motor neuron disease were diagnosed. As repeated high-dose intravenous methylprednisolone administration followed by oral tapering improved both central nervous system and lower motor neuron symptoms, the question was raised whether there was a common autoimmune pathogenesis of both clinically distinct diseases.

Cerebral Cortex↗

PubMed1993

Primary structure, neural-specific expression, and dendritic location of human BC200 RNA.

Primate BC200 RNA is a 200-nucleotide-long, nontranslatable RNA that is prevalently expressed in the nervous system. We have determined the primary structure of human BC200 RNA, using cDNA cloning and PCR techniques. BC200 RNA can be subdivided into three structural domains. The 5' region is homologous to Alu repetitive elements that are found in high copy numbers in primate genomes. The central part of BC200 RNA is characterized by a high percentage of A-residues, with a few interspersed other nucleotides. The 3' sequence is unique to BC200 RNA and shows no apparent similarity with known human DNA sequences. Sequence similarity with rodent BC1 RNA is limited to several short elements, and BC1/BC200 sequence comparisons indicate that the two genes have evolved via separate phylogenetic routes. Probes directed against the 3' unique part of BC200 RNA detected a single band corresponding to approximately 200 nucleotides on RNA blots. This band was identified only with RNA isolated from human brain, not with RNA from non-neural organs such as lung or kidney. In situ hybridization to selected areas of the human nervous system showed that BC200 RNA is expressed by a subpopulation of neurons that is analogous to the BC1 RNA-expressing subset of neurons in the corresponding areas of the rat nervous system. Moreover, like rat BC1 RNA, human BC200 RNA was localized to dendrite-rich neuropil areas, for example, in the inner plexiform layer of the retina. These results indicate that BC1 RNA and BC200 RNA, although of different evolutionary pedigree, may play analogous functional roles, in rodents and primates, respectively, in somatodendritic domains of nerve cells.

Base Sequence↗

PubMed1996

Inactivation of the first nucleotide-binding fold of the sulfonylurea receptor, and familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy is a disorder of glucose homeostasis and is characterized by unregulated insulin secretion and profound hypoglycemia. Loss-of-function mutations in the second nucleotide-binding fold of the sulfonylurea receptor, a subunit of the pancreatic-islet beta-cell ATP-dependent potassium channel, has been demonstrated to be causative for persistent hyperinsulinemic hypoglycemia of infancy. We now describe three additional mutations in the first nucleotide-binding fold of the sulfonylurea-receptor gene. One point mutation disrupts the highly conserved Walker A motif of the first nucleotide-binding-fold region. The other two mutations occur in noncoding sequences required for RNA processing and are predicted to disrupt the normal splicing pathway of the sulfonylurea-receptor mRNA precursor. These data suggest that both nucleotide-binding-fold regions of the sulfonylurea receptor are required for normal regulation of beta-cell ATP-dependent potassium channel activity and insulin secretion.

ATP-Binding Cassette Transporters↗

PubMed2006

Crystal structures of the thi-box riboswitch bound to thiamine pyrophosphate analogs reveal adaptive RNA-small molecule recognition.

Riboswitches are noncoding mRNA elements that bind small-molecule metabolites with high affinity and specificity, and they regulate the expression of associated genes. The thi-box riboswitch can exhibit a 1000-fold higher affinity for thiamine pyrophosphate over closely related noncognate compounds such as thiamine monophosphate. To understand the chemical basis of thi-box pyrophosphate specificity, we have determined crystal structures of an E. coli thi-box bound to thiamine pyrophosphate, thiamine monophosphate, and the structural analogs benfotiamine and pyrithiamine. When bound to monophosphorylated compounds, the RNA elements that recognize the thiamine and phosphate moieties of the ligand move closer together. This allows the riboswitch to recognize the monophosphate in a manner similar to how it recognizes the beta-phosphate of thiamine pyrophosphate. In the pyrithiamine complex, the pyrophosphate binding site is largely unstructured. These results show how the riboswitch can bind to various metabolites, and why the thi-box preferentially binds thiamine pyrophosphate.

Crystallography, X-Ray↗

PubMed1993

Nested polymerase chain reaction for high-sensitivity detection of enteroviral RNA in biological samples.

A method based on nested polymerase chain reaction was developed for the detection of enteroviral genomes in biological samples. By taking advantage of the conserved 5' noncoding region of the enteroviral RNA, two sets of primers were utilized, enabling the detection either of a broad range of enteroviruses or of group B coxsackieviruses only. The sensitivity of the method is close to the detection of single molecules of viral RNA in as much as 1 mg of tissue sample. A preliminary study showed the usefulness of this technique for the analysis of endomyocardial biopsy samples from patients with idiopathic dilated cardiomyopathy and myocarditis.

Base Sequence↗

PubMed2004

Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator.

Nuclear receptors (NRs) induce transcription through association with coactivator complexes. We identified a pseudouridine synthase (PUS), mPus1p, as a coactivator for retinoic acid receptor (mRAR)gamma and other NR-dependent transactivation. mPus1p is a member of the truA subfamily of PUSs, a class of enzymes that isomerize uridine to pseudouridine in noncoding RNAs, such as tRNA, to ensure proper folding and function. mPus1p binds the first zinc finger of mRARgamma and also associates with other NRs. Interestingly, mPus1p pseudouridylates coactivator Steroid Receptor RNA Activator (SRA), and when coexpressed, mPus1p and SRA cooperatively enhance mRARgamma-mediated transcription. mPus1p, mRARgamma, and SRA exist in a retinoid-independent, promoter bound complex in the nucleus although mPus1p is also expressed in the nucleolus, where it likely modifies tRNA. Finally, we show that mPus1p-coactivator function required SRA, mPus1p-associated mRARgamma binding, and PUS activities. mPus1p-dependent pseudouridylation of SRA represents an additional type of posttranscriptional modification of a NR-coactivator complex that is important for NR signaling.

Animals↗

PubMed2005

Global analysis of yeast RNA processing identifies new targets of RNase III and uncovers a link between tRNA 5' end processing and tRNA splicing.

We used a microarray containing probes that tile all known yeast noncoding RNAs (ncRNAs) to investigate RNA biogenesis on a global scale. The microarray verified a general loss of Box C/D snoRNAs in the TetO7-BCD1 mutant, which had previously been shown for only a handful of snoRNAs. We also monitored the accumulation of improperly processed flank sequences of pre-RNAs in strains depleted for known RNA nucleases, including RNase III, Dbr1p, Xrn1p, Rat1p and components of the exosome and RNase P complexes. Among the hundreds of aberrant RNA processing events detected, two novel substrates of Rnt1p (the RUF1 and RUF3 snoRNAs) were identified. We also identified a relationship between tRNA 5' end processing and tRNA splicing, processes that were previously thought to be independent. This analysis demonstrates the applicability of microarray technology to the study of global analysis of ncRNA synthesis and provides an extensive directory of processing events mediated by yeast ncRNA processing enzymes.

Gene Expression Regulation, Fungal↗

PubMed2024

CRISPRi screens identify the lncRNA, LOUP, as a multifunctional locus regulating macrophage differentiation and inflammatory signaling.

Long noncoding RNAs (lncRNAs) account for the largest portion of RNA from the transcriptome, yet most of their functions remain unknown. Here, we performed two independent high-throughput CRISPRi screens to understand the role of lncRNAs in monocyte function and differentiation. The first was a reporter-based screen to identify lncRNAs that regulate TLR4-NFkB signaling in human monocytes and the second screen identified lncRNAs involved in monocyte to macrophage differentiation. We successfully identified numerous noncoding and protein-coding genes that can positively or negatively regulate inflammation and differentiation. To understand the functional roles of lncRNAs in both processes, we chose to further study the lncRNA LOUP [lncRNA originating from upstream regulatory element of SPI1 (also known as PU.1)], as it emerged as a top hit in both screens. Not only does LOUP regulate its neighboring gene, the myeloid fate-determining factor SPI1, thereby affecting monocyte to macrophage differentiation, but knockdown of LOUP leads to a broad upregulation of NFkB-targeted genes at baseline and upon TLR4-NFkB activation. LOUP also harbors three small open reading frames capable of being translated and are responsible for LOUP's ability to negatively regulate TLR4/NFkB signaling. This work emphasizes the value of high-throughput screening to rapidly identify functional lncRNAs in the innate immune system.

RNA, Long Noncoding↗

PubMed1978

Complete sequence of constant and 3' noncoding regions of an immunoglobulin mRNA using the dideoxynucleotide method of RNA sequencing.

Three synthetic oligonucleotides were prepared to be complementary to known regions of the mouse immunoglublin light chain mRNA, and their ability to prime the transcription of complementary DNA (cDNA) was studied. The sequence of the cDNA was determined by adapting for mRNA the DNA sequencing method of Sanger, Nicklen and Coulson (1977) which uses 2'3' dideoxy ribonucleotides. A continuous sequence of 532 nucleotides was obtained, 321 corresponding to the whole of the constant region of the mRNA and the remaining 211 being the complete 3' noncoding region of the mRNA. The termination codon U-A-G occurs at the expected position in the mRNA corresponding to the triplet following the C terminal cystine. The nucleotide sequence is partially corroborated by the sequence of fragments obtained previously from 32P-mRNA fingerprints and endonuclease IV digests of 32P-cDNA, and is in agreement with the amino acid sequence of the constant region, except for a rearrangement of four amino acids (between amino acid positions 163 and 166). A revision of the amino acid sequence confirms the nucleic acid sequence.

Amino Acid Sequence↗

PubMed2004

Direct role of a viroid RNA motif in mediating directional RNA trafficking across a specific cellular boundary.

The plasmodesmata and phloem form a symplasmic network that mediates direct cell-cell communication and transport throughout a plant. Selected endogenous RNAs, viral RNAs, and viroids traffic between specific cells or organs via this network. Whether an RNA itself has structural motifs to potentiate trafficking is not well understood. We have used mutational analysis to identify a motif that the noncoding Potato spindle tuber viroid RNA evolved to potentiate its efficient trafficking from the bundle sheath into mesophyll that is vital to establishing systemic infection in tobacco (Nicotiana tabacum). Surprisingly, this motif is not necessary for trafficking in the reverse direction (i.e., from the mesophyll to bundle sheath). It is not required for trafficking between other cell types either. We also found that the requirement for this motif to mediate bundle sheath-to-mesophyll trafficking is dependent on leaf developmental stages. Our results provide genetic evidence that (1) RNA structural motifs can play a direct role in mediating trafficking across a cellular boundary in a defined direction, (2) the bundle sheath-mesophyll boundary serves as a novel regulatory point for RNA trafficking between the phloem and nonvascular tissues, and (3) the symplasmic network remodels its capacity to traffic RNAs during plant development. These findings may help further studies to elucidate the interactions between RNA motifs and cellular factors that potentiate directional trafficking across specific cellular boundaries.

Base Sequence↗

PubMed1996

Alternate splicing of the rTS gene product and its overexpression in a 5-fluorouracil-resistant cell line.

rTS is a gene with convergent and overlapping transcription relative to thymidylate synthase (TS). Screening of a cDNA library has identified a second rTS RNA (rTSbeta) which is related to a previously described rTS RNA (rTSalpha). rTSbeta differs from rTSalpha by the insertion of an extra 116 nucleotides after base 128 of rTSalpha and an altered 3'-noncoding region such that rTSbeta RNA is not complementary to TS mRNA. rTSalpha and rTSbeta RNAs have open reading frames predicted to encode proteins of 361 and 416 amino acids, respectively. Antibody to rTSbeta protein detects two proteins of the predicted molecular weight in the H630 colon tumor cell line. rTSbeta is overexpressed 40-70-fold in a 5-fluorouracil-resistant H630 subline compared with 7-8-fold for TS and rTSalpha.

Alternative Splicing↗

PubMed2001

Structure of an RNA hairpin from HRV-14.

The 5' noncoding region of the picornaviral genome begins with a cloverleaf which is required for viral replication, due at least in part to an interaction with the viral RNA polymerase as part of a fusion with the predominant viral protease. The necessary region of the cloverleaf has previously been narrowed to a highly conserved stem-loop. The solution structure of a 14-nucleotide RNA hairpin, which is part of the conserved stem-loop from human rhinovirus isotype 14, is presented here. The secondary structure of the hairpin is identical to predictions: a five base pair stem is bounded by a triloop with sequence UAU. However, the fold of the triloop is novel, with stacking of the second loop base onto the closing base pair of the stem, and deviations from A form geometry are introduced into the stem regions bordering the triloop, particularly on the 3' side. These deviations and the associated triloop structure could help to explain the distinct sequence conservation and mutational analysis data observed for the stem region of the hairpin, as compared to a second sequentially similar stem in the intact stem-loop.

5' Untranslated Regions↗

PubMed1990

Camptothecin-stabilized topoisomerase I-DNA adducts cause premature termination of transcription.

The antitumor agent camptothecin stabilizes type I topoisomerase-DNA complexes. One of the primary cellular responses to camptothecin exposure is rapid cessation of RNA synthesis. Results obtained by using an in vitro transcription system supplemented with eukaryotic topoisomerase I show that this inhibition can be attributed to physical blockage of the RNA polymerase by camptothecin-stabilized topoisomerase I-DNA complexes on the DNA template. The site of premature termination is located 10 base pairs upstream of the topoisomerase I linked nucleotide residue on the coding strand, corresponding closely to the border of the protected area obtained in a micrococcus nuclease footprint of topoisomerase I. The RNA polymerase transcribes unimpeded through complexes attached to the noncoding strand. No inhibitory effect of camptothecin on RNA transcription was observed with human topoisomerase I isolated from a camptothecin-resistant cell line. Taken together, the data suggest that part of the cytotoxicity of camptothecin is mediated through adduct formation on transcribed DNA, resulting in interference with transcriptional elongation.

Base Sequence↗

PubMed1989

Analysis of sequences involved in cowpea mosaic virus RNA replication using site-specific mutants.

Using a full-length cDNA clone of cowpea mosaic virus (CPMV) B-RNA from which infectious transcripts can be generated, we examined the influence of a sequence of 11 nucleotides, UUUUAUUAAAA, comprising the nucleotides 5883 to 5893 in the 3' noncoding region of B-RNA, on viral RNA replication. This sequence is not only present in B-RNA but also in M-RNA and represents the 7 nucleotides preceding the poly(A) tail and the first four A residues of the poly(A) tail. Replication of B-RNA transcripts derived from a series of mutants in this region was tested in cowpea plants and protoplasts. Only mutant transcripts with minor modifications appeared able to replicate, which indicates that the region has a function in viral RNA replication. In addition, the results suggest the existence of a hairpin loop in this region. Those transcripts with deletions which disturb the putative hairpin structure have decreased specific infectivities. Mutant transcripts reversed stepwise to the wild-type sequence during replication in plants. This observation strengthens the idea that the sequence of 11 nucleotides has a function in viral RNA replication.

Base Sequence↗