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Results for “RNA, Long Noncoding”

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PubMed2006

Hematopoietic precursor cells transiently reestablish permissiveness for X inactivation.

Xist is the trigger for X inactivation in female mammals. The long noncoding Xist RNA localizes along one of the two female X chromosomes and initiates chromosome-wide silencing in the early embryo. In differentiated cells, Xist becomes dispensable for the maintenance of the inactive X, and its function for initiation of silencing is lost. How Xist mediates gene repression remains an open question. Here, we use an inducible Xist allele in adult mice to identify cells in which Xist can cause chromosome-wide silencing. We show that Xist has the ability to initiate silencing in immature hematopoietic precursor cells. In contrast, hematopoietic stem cells and mature blood cells are unable to initiate ectopic X inactivation. This indicates that pathways critical for silencing are transiently activated in hematopoietic differentiation. Xist-responsive cell types in normal female mice show a change of chromatin marks on the inactive X. However, dosage compensation is maintained throughout hematopoiesis. Therefore, Xist can initiate silencing in precursors with concomitant maintenance of dosage compensation. This suggests that Xist function is restricted in development by the limited activity of epigenetic pathways rather than by a change in the responsiveness of chromatin between embryonic and differentiated cell types.

Alleles↗
PubMed2002

Chromosomal silencing and localization are mediated by different domains of Xist RNA.

The gene Xist initiates the chromosomal silencing process of X inactivation in mammals. Its product, a noncoding RNA, is expressed from and specifically associates with the inactive X chromosome in female cells. Here we use an inducible Xist expression system in mouse embryonic stem cells that recapitulates long-range chromosomal silencing to elucidate which Xist RNA sequences are necessary for chromosomal association and silencing. We show that chromosomal association and spreading of Xist RNA can be functionally separated from silencing by specific mutations. Silencing requires a conserved repeat sequence located at the 5' end of Xist. Deletion of this element results in Xist RNA that still associates with chromatin and spreads over the chromosome but does not effect transcriptional repression. Association of Xist RNA with chromatin is mediated by functionally redundant sequences that act cooperatively and are dispersed throughout the remainder of Xist but show little or no homology.

Animals↗
PubMed2025

LncRAnalyzer: a robust workflow for long non-coding RNA discovery using RNA-Seq.

Long non-coding RNA (lncRNA) is a major transcript category that lacks protein-coding capabilities, with relatively low abundance and complex expression patterns. Distinguishing lncRNAs from protein-coding genes is a complex process involving multiple filtering steps. We developed an automated pipeline named LncRAnalyzer featuring retrained models for 60 species. This workflow aims to reduce the likelihood of obtaining protein-coding or partial protein-coding transcripts during lncRNA identification by utilizing eight distinct approaches. We conducted a 10-fold cross-validation of the sorghum models and training sets with their standard ones and other approaches using real-life RNA-Seq datasets and known lncRNA and CDS sequences of sorghum. The results showed that the sorghum models and training sets were outperformed. The pipeline output comprises upset plots illustrating the number of lncRNA/NPCTs identified by the approaches, commonly identified lncRNA and their classes, NPCTs, and expression count tables. A feature-level comparison and benchmarking analysis of LncRAnalyzer with four existing pipelines, namely, LncPipe, LncEvo, lncRNA-Annotation, and Plant-LncPipe, demonstrated that LncRAnalyzer is more comprehensive, easier to implement, and accurate in lncRNA predictions. This workflow also ascertains lncRNA origins from various Transposable Elements (TEs) in plants using TE annotations from APTEdb [http://apte.cp.utfpr.edu.br/]. LncRAnalyzer is publicly available on GitLab [https://gitlab.com/nikhilshinde0909/LncRAnalyzer.git] for academic users.

RNA, Long Noncoding↗
PubMed2005

Analysis of the Xist RNA isoforms suggests two distinctly different forms of regulation.

The noncoding RNA Xist has been shown to direct the mammalian dosage compensation pathway. Expression of the Xist RNA is regulated through an uncharacterized post-transcriptional mechanism, thought to involve Xist RNA stability. We have previously demonstrated that Xist RNA isoforms contain different 3' ends. In this report we analyze the expression patterns of Xist RNA isoforms and show the Xist RNA long form (L-isoform) is the predominant form in early development. Significant amounts of both the short form (S-isoform) and the L-isoform were found in the female soma. We also define the precise sequence structure of the Xist RNA isoforms 3' ends and show the S-isoform and the L-isoform are structurally dissimilar. Our data show both the S-isoform and L-isoform are cleaved from the same primary transcript. However, the S-isoform is subsequently post-transcriptionally polyadenylated, while the L-isoform is not post-transcriptionally polyadenylated. Sequence organization of the L-isoform shows that there are at least five different nonadenylated L-isoforms in the female soma and only one in embryonic stem (ES) cells. This stem cell-and somatic cell-specific processing may suggest a role for Xist RNA processing in the regulation of Xist RNA expression.

Animals↗
PubMed2006

Alternative splicing of the first intron of the steroid receptor RNA activator (SRA) participates in the generation of coding and noncoding RNA isoforms in breast cancer cell lines.

The Steroid Receptor RNA Activator 1 (SRA1) has originally been described as a noncoding RNA specifically activating steroid receptor transcriptional activity. We have, however, identified, in human breast tissue, exon- 1 extended SRA1 isoforms containing two initiating AUG codons and encoding a protein we called SRAP. We recently reported a decreased estrogen receptor activity in breast cancer cells overexpressing SRAP, suggesting antagonist roles played by SRA1 RNA and SRAP. SRA1 appears to be the first example of a molecule active both at the RNA and at the protein level. No data are currently available regarding the mechanisms possibly involved in the generation of coding and noncoding functional SRA1 RNAs. Using 5'-Rapid Amplification of cDNA Extremities (5'-RACE), we have herein identified several putative transcription initiation sites surrounding the second methionine codon and used to generate coding SRA1 transcripts. In the process, we also identified an alternatively spliced noncoding SRA1 transcript still containing an intron-1 sequence. Using targeted RT-PCR approaches, we confirmed the presence in breast cancer cell lines of SRA1 RNAs containing a full as well as a partial intron-1 sequence and established that the relative proportion of these RNAs varied within breast cancer cell lines. Using a "minigene" strategy, we also showed that artificial RNAs containing the SRA1 intron-1 sequence are alternatively spliced in breast cancer cell lines. Interestingly, the splicing pattern of the minigene products parallels the one of the endogenous SRA1 transcripts. Altogether, our data suggest that the primary genomic sequence in and around intron-1 is sufficient to lead to a differential splicing of this intron. We propose that alternative splicing of intron-1 is one mechanism used by breast cancer cells to regulate the balance between coding and functional noncoding SRA1 RNAs.

Alternative Splicing↗
PubMed2002

Enox, a novel gene that maps 10 kb upstream of Xist and partially escapes X inactivation.

Dosage compensation in mammals is accomplished by the transcriptional silencing of a single X chromosome in female cells, a process termed X inactivation. A cytogenetically defined region of the X chromosome, the X-inactivation center (Xic), is necessary in cis for this process. Although the precise nature of the Xic remains unknown, a key component, the Xist gene, has been shown to be essential for X inactivation. In XX somatic cells, Xist RNA is specifically transcribed from the inactive X chromosome, which is otherwise essentially heterochromatic. Previous studies aimed at defining the proximal limit of the Xic have indicated that it lies within 30 kb upstream of the Xist promoter. Here we describe a novel gene, Enox (expressed neighbor of Xist), that maps to an unmethylated CpG island 10 kb upstream of Xist. Enox transcripts are antisense relative to Xist, highly heterogeneous, and apparently noncoding. In female somatic tissue Enox partially escapes from X inactivation. We discuss the implications of these findings in relation to our understanding of the Xic.

Animals↗
PubMed2000

The role of chromosomal RNAs in marking the X for dosage compensation.

Both flies and mammals remodel the architecture of the X chromosome to achieve dosage compensation. A novel class of noncoding RNAs that paint entire chromosomes are centrally involved in this process. The genes encoding these unusual RNAs are themselves located on the X, and are key sites that target the X for dosage compensation.

Animals↗
PubMed2005

Identification and characterization of a novel, psoriasis susceptibility-related noncoding RNA gene, PRINS.

To identify genetic factors contributing to psoriasis susceptibility, gene expression profiles of uninvolved epidermis from psoriatic patients and epidermis from healthy individuals were compared. Besides already characterized genes, we identified a cDNA with yet unknown functions, which we further characterized and named PRINS (Psoriasis susceptibility-related RNA Gene Induced by Stress). In silico structural and homology studies suggested that PRINS may function as a noncoding RNA. PRINS harbors two Alu elements, it is transcribed by RNA polymerase II, and it is expressed at different levels in various human tissues. Real time reverse transcription-PCR analysis showed that PRINS was expressed higher in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesional and healthy epidermis, suggesting a role for PRINS in psoriasis susceptibility. PRINS is regulated by the proliferation and differentiation state of keratinocytes. Treatment with T-lymphokines, known to precipitate psoriatic symptoms, decreased PRINS expression in the uninvolved psoriatic but not in healthy epidermis. Real time reverse transcription-PCR analysis showed that stress signals such as ultraviolet-B irradiation, viral infection (herpes simplex virus), and translational inhibition increased the RNA level of PRINS. Gene-specific silencing of PRINS by RNA interference revealed that down-regulation of PRINS impairs cell viability after serum starvation but not under normal serum conditions. Our findings suggest that PRINS functions as a noncoding regulatory RNA, playing a protective role in cells exposed to stress. Furthermore, elevated PRINS expression in the epidermis may contribute to psoriasis susceptibility.

Base Sequence↗
PubMed2001

PNA interference mapping demonstrates functional domains in the noncoding RNA Xist.

The noncoding RNA Xist has been shown to be essential for X-chromosome inactivation and to coat the inactive X-chromosome (Xi). Thus, an important question in understanding the formation of Xi is whether the binding reaction of Xist is necessary for X-chromosome inactivation. In this article, we demonstrate the failure of X-chromosome silencing if the association of Xist with the X-chromosome is inhibited. The chromatin-binding region was functionally mapped and evaluated by using an approach for studying noncoding RNA function in living cells that we call peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA caused the disruption of the Xi. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.

Animals↗
PubMed2006

Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.

We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance. We now report a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurological phenotype with in vivo imaging showing reduced cerebellar-cortical inhibition. 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction. The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels.

Animals↗
PubMed2002

Proteomics of breast cancer: outcomes and prospects.

Breast cancer is a major public health problem. The identification of new markers to differentiate neoplastic from the normal cells, more thorough understanding of different stages of the pathology, as well as the definition of new therapeutic targets, are all of critical importance. With the completion of human genome sequencing and the introduction of mass spectrometry, combined with protein identification via advanced bioinformatics, proteomics has emerged as a valuable tool for the discovery of new molecular markers. New methods in functional proteomics have also been developed to study the intracellular signaling pathways that underline the development of breast cancer. As illustrated with the examples of fibroblast growth factor-2 and H19, an oncogenic, noncoding mRNA, proteomics have become a powerful approach for deciphering the complex signaling circuitry involved in tumor growth. Breast cancer proteomics have already identified proteins of potential clinical interest (such as the molecular chaperone 14-3-3 sigma) and technological innovations in large scale/high throughput analysis are now ushering in new prospects.

Breast Neoplasms↗
PubMed2006

Molecular characterization and expression of maternally expressed gene 3 (Meg3/Gtl2) RNA in the mouse inner ear.

The pathways responsible for sound perception in the cochlea involve the coordinated and regulated expression of hundreds of genes. By using microarray analysis, we identified several transcripts enriched in the inner ear, including the maternally expressed gene 3 (Meg3/Gtl2), an imprinted noncoding RNA. Real-time PCR analysis demonstrated that Meg3/Gtl2 was highly expressed in the cochlea, brain, and eye. Molecular studies revealed the presence of several Meg3/Gtl2 RNA splice variants in the mouse cochlea, brain, and eye. In situ hybridizations showed intense Meg3/Gtl2 RNA staining in the nuclei of type I spiral ganglion cells and in cerebellum near the dorsal vestibular region of the cochlea. In embryonic mouse head sections, Meg3/Gtl2 RNA expression was observed in the otocyst, brain, eye, cartilage, connective tissue, and muscle. Meg3/Gtl2 RNA expression increased in the developing otocyst and localized to the spiral ganglion, stria vascularis, Reissner's membrane, and greater epithelial ridge (GER) in the cochlear duct. RT-PCR analysis performed on cell lines derived from the organ of Corti, representing neural, supporting, and hair cells, showed significantly elevated levels of Meg3/Gtl2 expression in differentiated neural cells. We propose that Meg3/Gtl2 RNA functions as a noncoding regulatory RNA in the inner ear and that it plays a role in pattern specification and differentiation of cells during otocyst development, as well as in the maintenance of a number of terminally differentiated cochlear cell types.

Animals↗
PubMed2006

Attenuated spread of X-inactivation in an X;autosome translocation.

X inactivation in female mammals involves transcriptional silencing of an entire chromosome in response to a cis-acting noncoding RNA, the X inactive-specific transcript (Xist). Xist can also inactivate autosomal sequences, for example, in X;autosome translocations; but here, silencing appears to be relatively inefficient. This variation has been attributed to either attenuated spreading of Xist RNA at the onset of X inactivation or inefficient maintenance of autosomal silencing. Evidence to date has favored the latter. Here, we demonstrate attenuated spreading of Xist RNA at the onset of X inactivation in the T(X;4)37H X;autosome translocation. Our findings provide direct evidence that underlying chromosome/chromatin features can disrupt spreading of the primary inactivating signal.

Animals↗
PubMed2003

Evolutionary constraints on the Disrupted in Schizophrenia locus.

The Disrupted in Schizophrenia (DISC) locus on human chromosome 1q42 has been strongly implicated by genetic studies as a susceptibility locus for major mental illnesses. In humans the locus is transcriptionally complex, with multiple alternate splicing events, antisense transcription, and intergenic splicing all evident. We have compared the genomic sequence and transcription maps of this locus between human, mouse, pufferfish (Fugu rubripes), and, in part, zebrafish (Danio rerio). The order and orientation of EGLN1, TSNAX, and DISC1 genes are conserved between mammals and F. rubripes. Intergenic splicing and short intergenic transcripts are not found to be conserved features. DISC2, a putative noncoding transcript partially antisense to DISC1, is not conserved in mouse or F. rubripes. Alternate splice forms of the protein-coding DISC1 gene are conserved even though the genomic structure is not. The amino acid sequence of DISC1 is diverging rapidly, although a putative nuclear localization signal and discrete blocks of coiled coil are specifically conserved features.

Amino Acid Sequence↗
PubMed2001

Epigenetic aspects of X-chromosome dosage compensation.

The X chromosomes of mammals and fruit flies exhibit unusual properties that have evolved to deal with the different dosages of X-linked genes in males (XY) and females (XX). The X chromosome dosage-compensation mechanisms discovered in these species are evolutionarily unrelated, but exhibit surprising parallels in their regulatory strategies. These features include the importance of noncoding RNAs, and epigenetic spreading of chromatin-modifying activities. Sex chromosomes have posed a fascinating puzzle for biologists. The dissimilar organization, gene content, and regulation of the X and Y chromosomes are thought to reflect selective forces acting on original pairs of identical chromosomes (1-3). The result in many organisms is a male-specific Y chromosome that has lost most of its original genetic content, and a difference in dosage of the X chromosome in males (XY) and females (XX).

Animals↗
PubMed2003

Forming facultative heterochromatin: silencing of an X chromosome in mammalian females.

Compensating for the dosage difference in X-linked genes between male and female mammals involves the formation of an extremely stable heterochromatin structure on one of the two X chromosomes in females. The inactive X acquires numerous features of silent chromatin, including the expression of a noncoding RNA, a switch to late replication, histone modifications, recruitment of the histone variant macroH2A and DNA hypermethylation. Although the induction of inactivation in differentiating mouse embryonic stem cells suggests that the onset of each of these features appears to occur in a sequential manner, it is likely that there is a much more complex interplay between the different features which leads to the extremely stable silencing observed in female somatic cells. Expression of the untranslated RNA, XIST, is required in cis for the establishment of the heterochromatic state. Recent results have started to elucidate how expression of Xist is controlled, including the role of the antisense transcript Tsix.

Animals↗
PubMed2006

The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene.

The Xist noncoding RNA is the key initiator of the process of X chromosome inactivation in eutherian mammals, but its precise function and origin remain unknown. Although Xist is well conserved among eutherians, until now, no homolog has been identified in other mammals. We show here that Xist evolved, at least partly, from a protein-coding gene and that the loss of protein-coding function of the proto-Xist coincides with the four flanking protein genes becoming pseudogenes. This event occurred after the divergence between eutherians and marsupials, which suggests that mechanisms of dosage compensation have evolved independently in both lineages.

Animals↗