Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “long noncoding RNA”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 937 records · Page 52Linked to original sources
PubMed2006

Imprinted gene expression in the rat embryo-fetal axis is altered in response to periconceptional maternal low protein diet.

In our previous study, we have shown that maternal low protein diet (LPD, 9% casein vs 18% casein control) fed exclusively during the rat preimplantation period (0-4.25 day postcoitum) induced low birth weight, altered postnatal growth and hypertension in a gender-specific manner. In this study, we investigated the effect of maternal LPD restricted only to the preimplantation period (switched diet) or provided throughout gestation on fetal growth and imprinted gene expression in blastocyst and fetal stages of development. Male, but not female, blastocysts collected from LPD dams displayed a significant reduction (30%) in H19 mRNA level. A significant reduction in H19 (9.4%) and Igf2 (10.9%) mRNA was also observed in male, but not in female, fetal liver at day 20 postcoitum in response to maternal LPD restricted to the preimplantation period. No effect on the blastocyst expression of Igf2R was observed in relation to maternal diet. The reduction in H19 mRNA expression did not correlate with an observed alteration in DNA methylation at the H19 differentially methylated region in fetal liver. In contrast, maternal LPD throughout 20 days of gestation did not affect male or female H19 and Igf2 imprinted gene expression in fetal liver. Neither LPD nor switched diet treatments affected H19 and Igf2 imprinted gene expression in day 20 placenta. Our findings demonstrate that one contributor to the alteration in postnatal growth induced by periconceptional maternal LPD may derive from a gender-specific programming of imprinted gene expression originating within the preimplantation embryo itself.

Animals↗
PubMed2005

The element(s) at the nontranscribed Xist locus of the active X chromosome controls chromosomal replication timing in the mouse.

In female mammalian cells, the inactive X chromosome is replicated late in S phase while the active X chromosome is replicated earlier. The replication times of the X chromosomes reflect a general trend in which late replication is associated with gene repression and earlier replication with transcriptional competence. The X-linked Xist gene is expressed exclusively from the inactive X chromosome where it is involved in the initiation and maintenance of X-inactivation. In contrast, no biological activity has been assigned to the Xist locus of the active X chromosome where the Xist gene is transcriptionally silenced. Here, we provide evidence that the element(s) at the nontranscribed Xist locus of the active X chromosome controls chromosomal replication timing in cis.

Animals↗
PubMed2006

A deletion at the mouse Xist gene exposes trans-effects that alter the heterochromatin of the inactive X chromosome and the replication time and DNA stability of both X chromosomes.

The inactive X chromosome of female mammals displays several properties of heterochromatin including late replication, histone H4 hypoacetylation, histone H3 hypomethylation at lysine-4, and methylated CpG islands. We show that cre-Lox-mediated excision of 21 kb from both Xist alleles in female mouse fibroblasts led to the appearance of two histone modifications throughout the inactive X chromosome usually associated with euchromatin: histone H4 acetylation and histone H3 lysine-4 methylation. Despite these euchromatic properties, the inactive X chromosome was replicated even later in S phase than in wild-type female cells. Homozygosity for the deletion also caused regions of the active X chromosome that are associated with very high concentrations of LINE-1 elements to be replicated very late in S phase. Extreme late replication is a property of fragile sites and the 21-kb deletions destabilized the DNA of both X chromosomes, leading to deletions and translocations. This was accompanied by the phosphorylation of p53 at serine-15, an event that occurs in response to DNA damage, and the accumulation of gamma-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.

Acetylation↗
PubMed2000

Methylated DNA sequences in genomic imprinting.

Genomic imprinting is a special form of epigenetic system that determines the parent-of-origin-specific, or monoallelic, expression of a small number of genes, termed "imprinted" genes. Considerable sequence and methylation analysis of imprinted genes has revealed a common theme: Regions of allele-specific methylation inherited from the gametes, or primary differentially methylated regions (DMRs), are associated with CpG islands and repeat elements, and this overall structure suggests functional significance. For at least three imprinted genes the sequence of the primary DMR constitutes an element able to regulate gene activity in cis--a chromatin insulator and a promoter of an antisense transcript. In these cases the unique feature of imprinting appears to be in the ability to switch the regulatory capacity of these elements on or off by the absence or presence of inherited methylation. Increasing evidence therefore suggests that genomic imprinting for at least some genes constitutes the regulation of gene regulatory elements by methylation. An important challenge now is to determine how the differential methylation of primary DMR sequences is established in the germ line. If methylation is the primary imprint, then the processes establishing it are the primary imprinting mechanisms. Trans-acting factors that are expressed in one sex of germ line and not the other are likely to be involved, and their ability to methylate may be mediated through repeat elements associated with the sequence of primary DMRs.

Alleles↗
PubMed2005

X-inactivation status varies in human embryonic stem cell lines.

Human embryonic stem cells (hESCs) derived from human blastocysts have an apparently unlimited proliferative capacity and can differentiate into ectoderm, mesoderm, and endoderm. As such, hESC lines have enormous potential for use in cell replacement therapies. It must first be demonstrated, however, that hESCs maintain a stable karyotype and phenotype and that gene expression is appropriately regulated. To date, different hESC lines exhibit similar patterns of expression of markers associated with pluripotent cells. However, the evaluation of epigenetic status of hESC lines has only recently been initiated. One example of epigenetic gene regulation is dosage compensation of the X chromosome in mammalian females. This is achieved through an epigenetic event referred to as X-chromosome inactivation (XCI), an event initiated upon cellular differentiation. We provide the first evidence that undifferentiated hESC lines exhibit different patterns of XCI.

Aneuploidy↗
PubMed2006

Methylation status of imprinting centers for H19/IGF2 and SNURF/SNRPN in primate embryonic stem cells.

Embryonic stem cells (ESCs) hold promise for cell and tissue replacement approaches to treating human diseases based on their capacity to differentiate into a wide variety of somatic cells and tissues. However, long-term in vitro culture and manipulations of ESCs may adversely affect their epigenetic integrity, including imprinting. We have recently reported aberrant biallelic expression of IGF2 and H19 in several rhesus monkey ESC lines, whereas SNRPN and NDN were normally imprinted and expressed predominantly from the paternal allele. The dysregulation of IGF2 and H19 that is associated with tumorigenesis in humans may result from improper maintenance of allele-specific methylation patterns at an imprinting center (IC) upstream of H19. To test this possibility, we performed methylation analysis of several monkey ESC lines by genomic bisulfite sequencing. We investigated methylation profiles of CpG islands within the IGF2/H19 IC harboring the CTCF-6 binding site. In addition, the methylation status of the IC within the promoter/exon 1 of SNURF/SNRPN known as the Prader-Willi syndrome IC was examined. Our results demonstrate abnormal hypermethylation within the IGF2/H19 IC in all analyzed ESC lines, whereas the SNURF/SNRPN IC was differentially methylated, consistent with monoallelic expression.

Animals↗
PubMed2005

Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas.

Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHB and SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novo promoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (P<0.001). This suggests that 11p15.5-imprinted genes may be implicated in the pathogenesis of both familial (germline VHL and SDHD mutations) and sporadic phaeochromocytomas.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Expression of IGF-II and H19 mRNA in the neonatal rat during normal maturation and after dexamethasone administration.

In this study, the expression of IGF-II and H19 was examined in the liver, skeletal muscle and choroid plexus of the neonatal rat during normal maturation and after the administration of dexamethasone. If the two genes share common regulatory elements as postulated by an enhancer competition system, their patterns of expression should remain similar throughout maturation and after treatment with dexamethasone. In the liver, down-regulation of IGF-II and H19 during maturation and after dexamethasone administration was shown. This is consistent with the hypothesis that IGF-II and H19 are regulated by common enhancers. In the secretory cells of the choroid plexus, where expression of IGF-II is known to be biallelic, IGF-II was expressed in both untreated and dexamethasone-treated animals, regardless of age, whereas H19 expression was not detectable. This is consistent with the postulate that only one gene from each allele can be engaged by the enhancers. In skeletal muscle, H19 continues to be expressed in the adult after IGF-II is switched off suggesting that IGF-II can also be regulated independently of H19.

Animals↗
PubMed2004

Estrogen response element-dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors.

One mechanism by which ligand-activated estrogen receptors alpha and beta (ERalpha and ERbeta) stimulate gene transcription is through direct ER interaction with specific DNA sequences, estrogen response elements (EREs). ERE-bound ER recruits coactivators that stimulate gene transcription. Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity, conformation, and transcriptional activity, indicating that the ERE sequence is an allosteric effector of ER action. Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors. CHO-K1 cells transfected with ERalpha or ERbeta show ERE sequence-dependent differences in the functional interaction of ERalpha and ERbeta with coactivators steroid receptor coactivator 1 (SRC-1), SRC-2 (glucocorticoid receptor interacting protein 1 (GRIP1)), SRC-3 amplified in breast cancer 1 (AIB1) and ACTR, cyclic AMP binding protein (CBP), and steroid receptor RNA activator (SRA), corepressors nuclear receptor co-repressor (NCoR) and silencing mediator for retinoid and thyroid hormone receptors (SMRT), and secondary coactivators coactivator associated arginine methyltransferase 1 (CARM1) and protein arginine methyltransferase 1 (PRMT1). We note both ligand-independent as well estradiol- and 4-hydroxytamoxifen-dependent differences in ER-coregulator activity. In vitro ER-ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell-based results, substantiating the importance of the full-length proteins in regulating ER activity. These data demonstrated that the ERE sequence impacts estradiol-and 4-hydroxytamoxifen-occupied ERalpha and ERbeta interaction with coregulators as measured by transcriptional activity in mammalian cells.

Amino Acid Sequence↗
PubMed2006

Rapid and quantitative method of allele-specific DNA methylation analysis.

Several biological phenomena depend on differential methylation of chromosomal strands. While understanding the role of these processes requires information on allele-specific methylation, the available methodologies are not quantitative or labor-intensive. We describe a novel, rapid method to quantitate allele-specific DNA methylation based on the combination of bisulfite PCR and Pyrosequencing. In this method, DNA is first treated with sodium bisulfite, which converts cytosine but not 5-methylcytosine to uracil. Genes of interest are subsequently amplified using PCR. Allele-specific methylation can then be determined by pyrosequencing each allele individually using sequencing primers that incorporate single nucleotide polymorphisms (SNPs) that allow differentiation between the two parental alleles. This allele-specific methylation methodology can potentially afford quantitative analyses relevant to the regulation of X chromosome inactivation, allele-specific expression of genes in the immune system, repetitive elements, and genomic imprinting. As an illustration of our new method, we quantitated allele-specific methylation of the differentially methylated region of the H19 gene, which is imprinted. Although we could reliably determine allele-specific methylation with our technique, additional studies will be required to confirm the ability of our assay to measure loss of imprinting.

Alleles↗
PubMed2001

Evidence that insulin is imprinted in the human yolk sac.

Allelic variation in the size of the insulin (INS) variable number tandem repeat (VNTR) correlates with the expression of both INS in the pancreas and thymus and IGF2 (the gene downstream of INS) in the placenta. In addition, the shorter, class I alleles are associated with type 1 diabetes, whereas the longer, class III alleles are associated with type 2 diabetes, polycystic ovary syndrome (PCOS), and size at birth. Parent-of-origin effects have been reported for type 2 diabetes and PCOS, thus implicating a role for genomic imprinting in these phenotypes. In mice, Ins2 is imprinted and paternally expressed in the yolk sac. In humans, evidence for the imprinting of INS is circumstantial, with occasional monoallelic expression in the thymus. In the present study, we found evidence for the imprinted paternal expression of INS in the human yolk sac. Two other imprinted genes from the same cluster are also expressed monoallelically in the human yolk sac. IGF2 was expressed solely from the paternal allele, and H19 was expressed solely from the maternal allele. These data suggest not only further functional roles for the human yolk sac in early fetal growth, but also evidence for a potential causal link between the control of insulin expression during development and insulin/growth-related diseases in later life.

Alleles↗
PubMed2000

The 5' repeat elements of the mouse Xist gene inhibit the transcription of X-linked genes.

X chromosome inactivation in mammals requires the Xist gene, which is exclusively expressed from the inactive X chromosome (Xi). The large heterogeneous Xist nuclear RNA colocalizes with Xi, most likely through nuclear protein interactions. The 5' region of the Xist RNA contains a series of well-conserved tandem repeats known to bind heteronuclear proteins in vitro and to enhance human XIST transcription. We show in an in vitro system that the conserved repeat element located in the 5' region of the mouse Xist gene (Xcr) represses three X-linked genes but has no effect on the autosomal genes Aprt, Ins, and the viral SV40 gene. The repression effect is not mediated by the conserved core sequence (Ccs) of Xcr, but requires the presence of the complete Xcr. This Xcr effect on X-linked genes suggests that Xcr transcript recognizes the genes to be silenced and is involved in the spreading of X inactivation.

Animals↗
PubMed2005

Hypomethylation of the XIST gene promoter in prostate cancer.

In a process denoted "global hypomethylation" repetitive DNA sequences like LINE-1 retrotransposons become hypomethylated in human cancers, including a subset of prostate carcinomas. It is less well known to what extent single-copy sequences are affected by this phenomenon. Therefore, we have analyzed methylation and expression of the XIST gene by bisulfite sequencing and real-time RT-PCR. The promoter of this single-copy gene is strongly methylated in normal male cells, including leukocytes and normal prostate. In prostate cancer tissues and particularly in cell lines, partial hypomethylation was observed paralleling that of LINE-1 sequences. Weak XIST expression was found in normal prostate tissues, but none in leukocytes. Only slight increases in expression of this gene were found in cancer tissues and cell lines. Our data suggest that hypomethylation in prostate cancer is indeed "global," affecting repeat and unique sequences in parallel. Detection of partially hypomethylated XIST alleles in prostate cancer tissues might be useful for the identification of cases with pronounced hypomethylation, which tend to be more aggressive.

Aged↗
PubMed2003

Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer.

AIM: NGX6, NAG-7 and BRD7 genes are tumor related genes, which have been newly cloned by positional candidate cloning strategy. This study was designed to investigate the expression levels of NGX6, NAG-7 and BRD7 genes in human gastric and colorectal cancer tissues, and their corresponding normal tissues, and to investigate whether these genes play a role in the pathogenesis of gastric and colorectal cancers. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR), dot hybridization and Northern blot analysis were used to compare the expression levels of NGX6, NAG-7 and BRD7 genes in 34 gastric cancer tissues and 34 colorectal cancer tissues with their corresponding normal tissues of the same patients, respectively. RESULTS: Among the 34 colorectal cancer specimens and the 34 gastric cancer specimens, the expression of NGX6 in 25 colorectal cancer tissues was absent or very weak (73.5 %) by RT-PCR analysis. The down-regulation rate of NGX6 in colorectal cancer tissues was significantly higher than that in corresponding normal tissues (26.5 %,9/34) (P<0.005). Moreover, the down-regulation of NGX6 was significantly correlated with lymph node and/or distance metastases. Patients with lymph node and/or distance metastasis had much higher down-regulation rate of NGX6 than patients without metastases (93.8 % vs 55.6 %, P<0.05). However no correlation was found between the expression of NGX6 and pathologic type of colorectal cancer in this study, and also the expression of NGX6 did not display any difference between gastric cancer and corresponding normal tissues (58.8 % vs 70.6 %, P>0.25). Dot hybridization and Northern blot analysis confirmed the results of RT-PCR. Furthermore, NAG-7 and BRD7 mRNA was not up- or down-regulated in gastric and colorectal cancers compared with their corresponding normal tissues in our study. CONCLUSION: The down-regulation of NGX6 may be closely associated with tumorigenesis and metastasis of colorectal carcinoma. However, it may not contribute to the development and progression of gastric carcinoma. In addition, the expression levels of NAG-7, and BRD7 did not alter in gastric and colorectal cancers. This seems to suggest that NAG-7 and BRD7 genes may not play a role in gastric and colorectal carcinogenesis.

Blotting, Northern↗
PubMed2000

Telomere length maintenance in aging and carcinogenesis.

Normal somatic cells have a finite number of divisions, a limited capacity to proliferate. Human telomeres, the long DNA TTAGGG repeats at the ends of chromosomes, are considered a molecular clock marker. The gradual and progressive telomere shortening at each replicative cycle is associated, through the activation of pRB and p53 pathways and genomic instability, to the replicative senescence, a non-dividing state and widespread cell death. Activation of telomere maintenance [telomerase; or alternative lengthening of telomeres mechanisms (ALT), or other adaptive responses] can revert this program. Although not completely known, several mechanisms and modulating agents may be able to up and down-regulate telomere length and its maintenance. Chemopreventive therapies for the up-regulation of telomerase activity, able to prolong the life of cell cultures in a phenotypically youthful state, could have important applications in research and medicine. On the contrary the therapeutic down-regulation of telomerase activity may be used in cancer therapy. Telomerase expression per se is not oncogenic, but telomere shortening and maintenance seem to be crucial events in tumor formation. Thus a particular focus has been pointed out relatively to the immortalization of normal or potential pre-cancerous cells. With the extension of life span the probability to get in contact with carcinogens increases, genetic instability, oncogene activation and/or onco-suppressor gene inactivation (i.e. p53, pRB, ras): the cancer transformation can be then induced in predisposed cells, depending on their genetic context, by the activation of telomere maintenance. Pharmacological intervention may be able to modulate the rate of living, by increasing life span of few specific target cells, or decreasing it in proliferating . Because of the unknown state of the enormous cell number of the human organism, is it safe to extend the human life span by therapeutic agents?

Aging↗
PubMed2001

Combination therapy of 2-5A antisense against telomerase RNA and cisplatin for malignant gliomas.

2',5'-Oligoadenylate (2-5A) linked to an antisense oligonucleotide against human telomerase RNA (2-5A-anti-hTR) is a novel therapeutic modality we have recently developed. We designed the oligonucleotide to target telomerase which maintains chromosome integrity in cancer cells. We have already demonstrated the efficacy of this new therapy in malignant glioma cells with telomerase activity. In the present study, we investigated the effect of 2-5A-anti-hTR in combination with cisplatin, an anti-cancer drug commonly used for malignant glioma patients. Six human malignant glioma cell lines with telomerase activity were treated with 0.5 microM 2-5A-anti-hTR and/or cisplatin (0, 0.1, 1, 5, 10, or 20 microg/ml) for three days, and cell viability was measured using the MTT colorimetric assay. The combination therapy showed synergistic effect at 1 microg/ml cisplatin and additive effect at 5 microg/ml cisplatin. TUNEL staining of the treated cells showed significantly increased apoptotic cells after the combination therapy. Furthermore, tumor growth of subcutaneous xenografts of human malignant glioma cells in nude mice was effectively reduced after the combination therapy for seven days. Our study shows that the tumor-killing effects of the combined treatments are, at least in part, due to induction of apoptosis. 2-5A-anti-hTR is a promising therapy not only when used alone, but also in combination with cisplatin.

Animals↗
PubMed2001

Examination of the oncogenic potential of H19 gene in HeLa x normal human fibroblast hybrid cells.

Fusion of tumorigenic HeLa cells with human skin fibroblasts results in chromosomally stable non-tumorigenic hybrids. The studies of rare spontaneous tumorigenic segregants from the non-tumorigenic hybrid have implicated the loss of one copy of human fibroblast chromosome 11 with concomitant re-expression of tumorigenicity. In a previous study of differential display screening, we reported the tumorigenic-specific expression of H19 gene as a possible candidate for elicitation of tumorigenic phenotype. In this study, we examined the expression of H19 gene using gamma-ray-induced tumorigenic mutants (GIMs) and non-tumorigenic irradiated control cells (CONs) from the non-tumorigenic hybrids. H19 expression was recognized in all the GIMs with various expression levels, whereas no CONs expressed the H19 gene. To examine the tumorigenic potentials of H19 gene directly, we introduced an H19 gene expression vector into the non-tumorigenic hybrids and assayed the tumorigenicity of the transfectants by s.c. injection into athymic nude mice. However, no transfectants with stable H19 gene expression induced in vivo tumor growth. These results suggest that expression of the H19 gene may be necessary but is not sufficient to confer the tumorigenic phenotype in HeLa x fibroblast hybrids.

Animals↗