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Results for “long noncoding RNA”

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At least 325 records · Page 18Linked to original sources
PubMed1998

H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression.

In a previous study we described the expression of the H19 gene by in situ hybridization (ISH) in normal breast and in benign or malignant breast tumors (Dugimont T, Curgy JJ, Wernert N, Delobelle A, Raes MB, Joubel A, Stehelin D, Coll J: Biol Cell 1995, 85:117-124). In the present work, 1) we extend the previous one to a statistically useful number of adenocarcinomas, including 10 subclasses, 2) we provide information on the precise ISH localization of the H19 RNA by using, on serial tissue sections, antibodies delineating specifically the stromal or the epithelial component of the breast, and 3) we consider relationships between the H19 gene expression and various clinicopathological information as tumor values (T0 to T4), grades, steroid receptors, lymph node status, and molecular features as the p53 gene product and the Ki-67/MIB1 protein, which is specific to proliferating cells. Data indicate that 1) in 72.5% of studied breast adenocarcinomas an overall H19 gene expression is increased when compared with healthy tissues, 2) the H19 gene is generally overexpressed in stromal cells (92.2%) and rarely in epithelial cells (2.9% only), 3) an up-regulation of the H19 gene is significantly correlated with the tumor values and the presence of both estrogen and progesterone receptors, and 4) at the cellular level, the H19 gene demonstrates an independent expression versus accumulation of both the p53 protein and the Ki-67/MIB-1 cell-cycle marker.

Adenocarcinoma↗
PubMed2003

Identification of new human coding steroid receptor RNA activator isoforms.

SRA is a steroid receptor co-activator which acts as a functional RNA and is classified as belonging to the growing family of functional non-coding RNAs. None of the different SRA transcripts described to date encode a detectable SRA protein following in vitro and in vivo translation experiments. We have identified three new SRA-RNA isoforms differing mainly from the originally cloned SRA by an extended 5(') extremity. These long SRA isoforms, able to encode a stable protein in vitro, led to the production in vivo of a nuclear protein when transfected into the MCF-7 human breast cancer cell line. Reverse-transcription polymerase chain reaction and Western blot analysis of RNA and protein extracts from different breast cancer cell lines confirmed the presence of endogenous coding SRA isoforms and their corresponding proteins. Our results demonstrate that full-length SRA-RNAs likely to encode stable proteins are widely expressed in breast cancer cell lines.

5' Flanking Region↗
PubMed2002

Growth signaling in breast cancer cells: outcomes and promises of proteomics.

Methods in functional proteomics are now used to study the intracellular signaling pathways that underlie the development of breast cancer. As shown with fibroblast growth factor-2, the oncogenic/non-coding mRNA H19 and 14-3-3 proteins, proteomics is a powerful approach to identify signaling proteins and to decipher the complex signaling circuitry involved in growth of breast cancer cells. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast cancerogenesis and to identify new therapeutic targets.

14-3-3 Proteins↗
PubMed1998

Biallelic expression of all four IGF-II promoters and its association with increased methylation of H19 gene in human brain.

The human IGF-II gene is maternally imprinted in all tissues except adult liver and the choroid plexus/leptomeninges of the central nervous system where IGF-II is biallelically expressed. In human liver, it has recently been reported that this biallelic expression only involves the promoter P1 while the promoters P2-P4 direct IGF-II transcription monoallelically. To explore whether or not biallelic expression of the IGF-II promoters in human CNS displays the same pattern as in liver, we examined the allelic expression status of the four IGF-II promoters in human brain. We found that all four IGF-II promoters in human fetal and adult brain were expressed from both parental alleles. Furthermore, the levels of methylation of the 3' region of H19 gene in fetal brain were higher than those in other tissues with monoallelic expression of IGF-II. Since similar findings have been reported in Wilms' tumor, these data suggest a similar mechanism may be responsible for loss of imprinting of IGF-II in normal brain and Wilms' tumor.

Adult↗
PubMed2000

Cloning and characterization of human histone deacetylase 8.

To date, seven different human histone deacetylases (HDACs) have been identified, which fall into two distinct classes. We have isolated and characterized a cDNA encoding a novel human HDAC, which we name HDAC8. HDAC8 shows a high degree of sequence similarity to HDAC1 and HDAC2 and thus belongs to the class I of HDACs. HDAC8 is expressed in a variety of tissues. Human cells overexpressing HDAC8 localize the protein in sub-nuclear compartments whereas HDAC1 shows an even nuclear distribution. In addition, the HDAC8 gene is localized on the X chromosome at position q13, which is close to the XIST gene and chromosomal breakpoints associated with preleukemia.

Amino Acid Sequence↗
PubMed2001

Relationship between DNA methylation, histone H4 acetylation and gene expression in the mouse imprinted Igf2-H19 domain.

DNA methylation and histone H4 acetylation play a role in gene regulation by modulating the structure of the chromatin. Recently, these two epigenetic modifications have dynamically and physically been linked. Evidence suggests that both modifications are involved in regulating imprinted genes - a subset of genes whose expression depends on their parental origin. Using immunoprecipitation assays, we investigate the relationship between DNA methylation, histone H4 acetylation and gene expression in the well-characterised imprinted Igf2-H19 domain on mouse chromosome 7. A systematic regional analysis of the acetylation status of the domain shows that parental-specific differences in acetylation of the core histone H4 are present in the promoter regions of both Igf2 and H19 genes, with the expressed alleles being more acetylated than the silent alleles. A correlation between DNA methylation, histone hypoacetylation and gene repression is evident only at the promoter region of the H19 gene. Treatment with trichostatin A, a specific inhibitor of histone deacetylase, reduces the expression of the active maternal H19 allele and this can be correlated with regional changes in acetylation within the upstream regulatory domain. The data suggest that histone H4 acetylation and DNA methylation have distinct functions on the maternal and paternal Igf2-H19 domains.

Acetylation↗
PubMed2003

Involvement of NF-Y and Sp1 binding sequences in basal transcription of the human telomerase RNA gene.

The proximal promoter of the telomerase RNA gene, hTR, contains four Sp1 sites and one CCAAT box. We have carried out a functional analysis of the role of these sequence elements. Two Sp1 sites downstream of the CCAAT box mediated negative regulation, while the other two Sp1 sites were positive regulators with the strongest effect mediated by the negative regulatory Sp1 site closely flanking the CCAAT box. Basal transcriptional activity is maintained via the CCAAT box even when all four Sp1 sites are mutated, suggesting nuclear factor-Y (NF-Y) is a fundamental regulator of hTR promoter function. Chromatin immunoprecipitation revealed binding of NF-Y, Sp1 and TFIIB to the promoter in vivo. Thus the interaction of NF-Y at the CCAAT box is pivotal to hTR gene transcription and surrounding sequence elements may provide an environment for the regulation of activity through recruitment of additional protein complexes.

Base Sequence↗
PubMed1998

The effect of retinoic acid on the activation of the human H19 promoter by a 3' downstream region.

The human H19 is paternally imprinted (maternally expressed). It is transcribed by RNA pol II, but has no protein product. Its function is unknown. We showed that the transcription of the human H19 gene is under the simultaneous control of both a 5' upstream (promoter) region and a 3' downstream region in cell lines derived from human choriocarcinomas. Moreover, the activation of the H19 promoter by retinoic acid in cells derived from human testicular germ cell tumors is dependent upon the 3' downstream region. The possibility that the action of retinoic acid on the H19 promoter is an indirect one and involves a member of the AP2 transcription factor family is discussed.

Antineoplastic Agents↗
PubMed1998

Loss of imprinting of IGF2 and not H19 in breast cancer, adjacent normal tissue and derived fibroblast cultures.

Insulin-like growth factors are involved in the paracrine growth regulation of human breast tumor cells. IGF2 is imprinted in most tissues, and shows expression of the paternal allele only. To investigate whether disruption of this monoallelic IGF2 expression is involved in breast cancer development, a series of primary tumors and adjacent, histologically normal, breast tissue samples, as well as matched primary in vitro fibroblast cultures were studied. Biallelic expression (partial) of IGF2 was found in the majority of in vivo samples, and corresponding fibroblast cultures, while monoallelic expression was found in a normal breast sample. In contrast, H19, a closely apposed, but reciprocally imprinted gene, assumed to be regulated by a common control element, showed retention of monoallelic H19 expression in all in vivo and in the majority of in vitro samples. These data indicate that IGF2, but not H19, is prone to loss of imprinting in breast cancer.

Breast↗
PubMed1999

The expression of the H19 gene and its function in human bladder carcinoma cell lines.

The human H19 gene is a paternally imprinted oncofetal gene, highly expressed in several fetal tissues, down-regulated in nearly all adult tissues but re-expressed in carcinomas of tissues which express the gene in fetal life. It has no known protein product and till today, no function could be designated to H19 RNA. Cells derived from bladder carcinomas and hepatocellular carcinomas were transfected with plasmids carrying a luciferase reporter gene under the control of a 800 nucleotides long promoter region of the H19 gene either alone or together with different parts of a 5 kb downstream region, previously shown to possess enhancer activity. Our results provide evidence that three regions of the 3' downstream sequence can independently stimulate the H19 promoter activity in a tissue and cell specific manner. The growth rate of two cell populations, both derived from the same bladder carcinoma cell line and which differ in their H19 RNA content, were compared. The cells with a high H19 RNA level stopped their proliferation after 48 h when cultivated in a low serum containing media while the cells lacking H19 RNA continued their proliferation for at least an additional 48 h period.

Gene Expression↗
PubMed1999

Role of histone acetylation and DNA methylation in the maintenance of the imprinted expression of the H19 and Igf2 genes.

H19 and Igf2 are linked and reciprocally imprinted genes. We demonstrate that the histones associated with the paternally inherited and unexpressed H19 allele are less acetylated than those associated with the maternal expressed allele. Cell growth in the presence of inhibitors of either histone deacetylase or DNA methylation activated the silent Igf2 allele, whereas derepression of the silent H19 allele required combined inhibition of DNA methylation and histone deacetylation. Our results indicate that histone acetylation as well as DNA methylation contribute to the somatic maintenance of H19 and Igf2 imprinting and that silencing of the imprinted alleles of these two genes is maintained via distinct mechanisms.

Acetylation↗
PubMed2003

Nucleosome positioning signals in the DNA sequence of the human and mouse H19 imprinting control regions.

We have investigated the sequences of the mouse and human H19 imprinting control regions (ICRs) to see whether they contain nucleosome positioning information pertinent to their function as a methylation-regulated chromatin boundary. Positioning signals were identified by an in vitro approach that employs reconstituted chromatin to comprehensively describe the contribution of the DNA to the most basic, underlying level of chromatin structure. Signals in the DNA sequence of both ICRs directed nucleosomes to flank and encompass the short conserved sequences that constitute the binding sites for the zinc finger protein CTCF, an essential mediator of insulator activity. The repeat structure of the human ICR presented a conserved array of strong positioning signals that would preferentially flank these CTCF binding sites with positioned nucleosomes, a chromatin structure that would tend to maintain their accessibility. Conversely, all four CTCF binding sites in the mouse sequence were located close to the centre of positioning signals that were stronger than those in their flanks; these binding sites might therefore be expected to be more readily incorporated into positioned nucleosomes. We found that CpG methylation did not effect widespread repositioning of nucleosomes on either ICR, indicating that allelic methylation patterns were unlikely to establish allele-specific chromatin structures for H19 by operating directly upon the underlying DNA-histone interactions; instead, epigenetic modulation of ICR chromatin structure is likely to be mediated principally at higher levels of control. DNA methylation did, however, both promote and inhibit nucleosome positioning at several sites in both ICRs and substantially negated one of the strongest nucleosome positioning signals in the human sequence, observations that underline the fact that this epigenetic modification can, nevertheless, directly and decisively modulate core histone-DNA interactions within the nucleosome.

Animals↗
PubMed2003

Transgene instability in mice injected with an in vitro methylated Igf2 gene.

Foreign DNA injected into mouse embryos integrates into the host chromosomes and is usually transmitted stably to the progeny. Rare cases of transgene instability have been described, and these can help our understanding of the rules that govern the organization and stability of endogenous DNA. We have observed unusual inheritance in three transgenic lines produced with a partially in vitro methylated Igf2 construct. All three founders transmitted to their progeny two different transgene patterns, A and B. Pattern A was inherited in accordance with expectation, whereas pattern B was associated with several abnormal characteristics, including fewer than expected transgenic progeny, evidence for instability and loss from the somatic tissues of some of the progeny, and high incidence of runting and perinatal death that did not appear correlated with transgene retention. The absence of these features in transgenic mice produced with the unmethylated version of the same construct indicated that prior methylation played a role in the unusual behavior of these transgenes. We hypothesize that patterns A and B were formed by transgenes that differed in their methylation, and that pattern B methylation led to instability of the transgene locus. Runting and early lethality in the pattern B sublines may be the result of transgene rearrangements, which result in transgene amplification with adverse effects of increased IGFII dosage, and/or deletions, which may affect endogenous genes required for viability. These findings provide further evidence that DNA methylation plays a role in genome stability and indicate that perturbations in the normal pattern of methylation may have destabilizing effects that extend through several generations.

Animals↗
PubMed1997

Loss of H19 imprinting and up-regulation of H19 and SNRPN in a case with malignant mixed Müllerian tumor of the uterus.

In several human cancers, it has been recently reported that abnormally altered status of genomic imprinting is related to oncogenesis. In this study, we investigated the expression of three imprinted genes in a case with malignant mixed Müllerian tumor of the uterus (MMMT). In the tumor, expression of H19 showed marked upregulation (6.3-fold) with biallelic expression compared with that in the corresponding normal myometrium. The 5'-promoter region of H19 was hypomethylated in the tumor, whereas it was hemimethylated in the myometrium. Expression of the small nuclear ribonucleoprotein polypeptide N gene (SNRPN) was also upregulated by 1.9-fold. However, the insulin-like growth factor II gene (IGF2) was expressed at low levels in both myometrium and MMMT. The overexpression of H19 is caused by reactivation of the repressed allele of H19 due to demethylation of CpG islands within its 5'-promoter region. Whether upregulation of SNRPN is caused by its biallelic expression remains undetermined because restriction fragment length polymorphisms (RFLP) sites were not informative in SNRPN and IGF2. In conclusion, H19 and SNRPN may play significant roles in the tumorigenesis of MMMT and H19 may have tumor-promoting activity in addition to its known tumor-suppressing activity, probably depending on the tissue and the local milieu.

Autoantigens↗
PubMed2004

Pharmacology of nuclear receptor-coregulator recognition.

The nuclear receptor (NR) superfamily comprises approximately 50 members that are responsible for regulating a number of physiologic processes in humans, including metabolism, homeostasis, and reproduction. Included in the superfamily are the receptors for steroids, lipophilic vitamins, bile acids, retinoids, and various fatty acids. NRs exert their action as transcription factors that directly bind to the promoters of target genes and regulate their rate of transcription. To modulate transcription, however, NRs must recruit a number of accessory coregulators known as corepressors and coactivators. These coregulators harbor a variety of activities, such as the ability to modify chromatin structure, interact with basal transcriptional machinery, and modify RNA splicing. Recent studies have revealed that the pharmacological characteristics of various NR ligands are regulated by their ability to modulate the coregulator interaction profile of an NR.

Animals↗