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Results for “Long noncoding RNA”

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At least 307 records · Page 17Linked to original sources

PubMed2003

The cell biology of a novel chromosomal RNA: chromosome painting by XIST/Xist RNA initiates a remodeling cascade.

X chromosome inactivation begins when a novel chromosomal RNA (cRNA) from the imprinted mouse Xist or human XIST locus coats or "paints" one X chromosome in cis and initiates a cascade of chromosome remodeling events. Molecular cytological studies have proven invaluable for understanding the distinctive cellular behavior of this singular RNA involved in chromosome structure and regulation. While the detailed mechanism of XIST/Xist (X-inactivation Specific Transcript) RNA function remains largely unknown, recent advances provide new insights into the complex cellular factors which impact the RNA's localization to the chromosome, as well as the early events of chromosome remodeling that follow painting by Xist RNA. Because chromatin changes can be directly visualized on a silenced chromosome, X chromosome inactivation provides an advantageous model to investigate genome-wide heterochromatin formation and maintenance, with wide-ranging implications for normal cells and disease.

Animals↗

PubMed2003

Beyond sense: the role of antisense RNA in controlling Xist expression.

The Xist RNA is a critical component of X inactivation, and Tsix is a non-coding antisense RNA to the Xist gene. We review the data from mouse that demonstrates that Tsix serves to regulate Xist expression. TSIX antisense transcripts have also been detected in humans, but without a manipulatable system to study the inactivation process in humans it remains unknown whether these antisense transcripts are functional in regulating human XIST. After a review of the differences between the human and mouse antisense, we discuss how the question of whether or not the human TSIX is functional impacts models of Tsix function.

Animals↗

PubMed2003

Controlling X-inactivation in mammals: what does the centre hold?

Controlling gene expression is one of the most fundamental task of living organisms, from prokaryotes to higher eukaryotes, in order to develop, grow, and reproduce in an ever changing environment. In many cases, the expression status of a given gene is controlled independently of that of its neighbours through localised cis DNA elements responsible for the recruitment of specific factors and enzymatic activities. However, in a growing number of cases, genomic regions including several genes have been shown to be regulated in a coordinated manner. X-chromosome inactivation, the dosage compensation mechanism encountered in mammals, is one of the most Striking example of such coordinated gene regulation. This process, which occurs at the chromosome-wide level, affecting many hundreds of genes, is under the control of a unique, cis acting region, termed the X-inactivation centre, whose complexity is just beginning to be unravelled.

Animals↗

PubMed2003

Barring gene expression after XIST: maintaining facultative heterochromatin on the inactive X.

X chromosome inactivation refers to the developmentally regulated process of silencing gene expression from all but one X chromosome per cell in female mammals in order to equalize the levels of X chromosome derived gene expression between the sexes. While much attention has focused on the genetic and epigenetic events early in development that initiate the inactivation process, it is also important to understand the events that ensure maintenance of the inactive state through subsequent cell divisions. Gene silencing at the inactive X chromosome is irreversible in somatic cells and is achieved through the formation of facultative heterochromatin (visible as the Barr body) that is remarkably stable and faithfully preserved. Here we review the many features of inactive X chromatin in terminally differentiated cells and address the highly redundant mechanisms of maintaining the inactive X chromatin.

Animals↗

PubMed2003

Imprinted X-chromosome inactivation: enlightenment from embryos in vivo.

There are two forms of X chromosome inactivation (XCI) in the laboratory mouse, random XCI in the fetus and imprinted paternal XCI limited to the extraembryonic tissues supporting the fetal life in utero. Imprinted XCI has been studied extensively because it takes place first in embryogenesis and it may hold clues to the mechanism of control of XCI in general and to the evolution of random' XCI. Classical microscopic and biochemical studies of embryos in vivo provide a basis for interpreting the multifaceted information yielded by various inventive approaches and for planning further experiments.

Animals↗

PubMed2006

Non-coding RNA in fly dosage compensation.

Dosage compensation modulates global expression of an X chromosome and is necessary to restore the balance between X-chromosome and autosome expression in both sexes. A central question in the field is how this regulation is directed. Large non-coding RNAs, such as Xist in mammals and roX in flies, have pivotal roles in targeting chromosome-wide modification for dosage compensation. Several recent studies in Drosophila provide new insight into the principles of X-chromosome recognition and the function of non-coding RNA in this process.

Animals↗

PubMed2004

Analysis of sex differences in EGC imprinting.

Sex-specific differences are apparent in the methylation patterns of H19 and Igf2 imprinted genes in embryonic germ cells (EGCs) derived from 11.5 or 12.5 days post coitum (dpc) primordial germ cells (PGCs). Here we studied whether these differences are associated either with the sex chromosome constitution of the EGCs or with the sex of the genital ridge (testis versus ovary) from which the PGCs were isolated. For this purpose we derived pluripotent EGC lines from sex-reversed embryos, either XY embryos deleted for Sry (XY(Tdym1)) or XX embryos carrying an Sry transgene. Southern blotting of the EGC DNA was used to analyze the differentially methylated regions of Igf2 and H19. The analysis revealed that both genes were more methylated in EGCs with an XY sex chromosome constitution than in those with an XX sex chromosome constitution, irrespective of the phenotypic sex of the genital ridge from which the EGCs had been derived. We conclude that the sex-specific methylation is intrinsic and cell-autonomous, and is not due to any influence of the genital ridge somatic cells upon the PGCs.

Animals↗

PubMed2005

X chromosome reactivation and regulation in cloned embryos.

Somatic cell nuclear transfer embryos exhibit extensive epigenetic abnormalities, including aberrant methylation and abnormal imprinted gene expression. In this study, a thorough analysis of X chromosome inactivation (XCI) was performed in both preimplantation and postimplantation nuclear transfer embryos. Cloned blastocysts reactivated the inactive somatic X chromosome, possibly in a gradient fashion. Analysis of XCI by Xist RNA and Eed protein localization revealed heterogeneity within cloned embryos, with some cells successfully inactivating an X chromosome and others failing to do so. Additionally, a significant proportion of cells contained more than two X chromosomes, which correlated with an increased incidence of tetraploidy. Imprinted XCI, normally found in preimplantation embryos and extraembryonic tissues, was not observed in blastocysts or placentae from later stage clones, although fetuses recapitulated the Xce effect. We conclude that, although SCNT embryos can reactivate, count, and inactivate X chromosomes, they are not able to regulate XCI consistently. These results illustrate the heterogeneity of epigenetic changes found in cloned embryos.

Animals↗

PubMed2006

X-tra! X-tra! News from the mouse X chromosome.

X chromosome inactivation (XCI) is the phenomenon through which one of the two X chromosomes in female mammals is silenced to achieve dosage compensation with males. XCI is a highly complex, tightly controlled and developmentally regulated process. The mouse undergoes two forms of XCI: imprinted, which occurs in all cells of the preimplantation embryo and in the extraembryonic lineage, and random, which occurs in somatic cells after implantation. This review presents results and hypotheses that have recently been proposed concerning important aspects of both imprinted and random XCI in mice. We focus on how imprinted XCI occurs during preimplantation development, including a brief discussion of the debate as to when silencing initiates. We also discuss regulation of random XCI, focusing on the requirement for Tsix antisense transcription through the Xist locus, on the regulation of Xist chromatin structure by Tsix and on the effect of Tsix regulatory elements on choice and counting. Finally, we review exciting new data revealing that X chromosomes co-localize during random XCI. To conclude, we highlight other aspects of X-linked gene regulation that make it a suitable model for epigenetics at work.

Animals↗

PubMed2004

Role of H19 3' sequences in controlling H19 and Igf2 imprinting and expression.

The regulation of H19 and Igf2 imprinting and expression depends on common elements. Using comparative analysis between human and mouse, we identified conserved regions 3' of the H19 transcription unit, including the H19/Igf2 endodermal enhancers and elements within a 4.2-kb domain between the H19 transcription unit and the enhancers. Transgene experiments implicate these elements in imprinting regulation. To establish whether they are required at the endogenous locus, first we replaced the endodermal enhancers with the alpha-fetoprotein endodermal enhancers (H19Afp). Second, we deleted the 4.2-kb region (H19delta4.2). Our analysis revealed that H19 and Igf2 imprinting and tissue-specific expression were maintained for both mutations, except for a slight reduction in paternal Igf2 expression from the H19Afp allele in liver. These results demonstrate that the H19 insulator can interact with heterologous enhancers to imprint Igf2. Furthermore, for H19, chromatin context or additional sequences possibly compensate for loss of conserved 3' elements.

3' Flanking Region↗

PubMed2004

Timing of establishment of paternal methylation imprints in the mouse.

Imprinted genes are characterized by predominant expression from one parental allele and differential DNA methylation. Few imprinted genes have been found to acquire a methylation mark in the male germ line, however, and only one of these, H19, has been studied in detail. We examined methylation of the Rasgrf1 and Gtl2 differentially methylated regions (DMR) to determine whether methylation is erased in male germ cells at e12.5 and when the paternal allele acquires methylation. We also compared their methylation dynamics with those of H19 and the maternally methylated gene Snrpn. Our results show that methylation is erased on Rasgrf1, H19, and Snrpn at e12.5, but that Gtl2 retains substantial methylation at this stage. Erasure of methylation marks on Gtl2 appears to occur later in female germ cells to give the unmethylated profile seen in mature MII oocytes. In the male germ line, de novo methylation of Rasgrf1, Gtl2, and H19 occurs in parallel between e12.5 and e17.5, but the DMR are not completely methylated until the mature sperm stage, suggesting a methylation dynamic different from that of IAP, L1, and minor satellite sequences, which have been shown to become fully methylated by e17.5 in male germ cells. This study also indicates important differences between different imprinted DMR in timing and extent of methylation in the germ cells.

Alleles↗

PubMed2005

High-resolution map and imprinting analysis of the Gtl2-Dnchc1 domain on mouse chromosome 12.

The imprinted Dlk1-Dio3 region on mouse chromosome 12 contains six imprinted genes and a number of maternally expressed snoRNAs and miRNAs. Here we present a high-resolution sequence analysis of the 1.1-Mb segment telomeric to Gtl2 in mouse and a homology comparison to the human. Ppp2r5c and Dnchc1 at the telomeric end of the analyzed sequence are biallelically expressed, suggesting that the imprinted domain does not extend beyond the paternally expressed Dio3 gene. RT-PCR experiments support the predicted presence of a maternally expressed intergenic transcript(s) encompassing Gtl2, Rian, and Mirg. These maternally expressed genes, and also the intergenic transcript(s), show pronounced expression in the adult mouse brain, whereas the paternally transcribed Dio3 and the nonimprinted Ppp2r5c and Dnchc1 are expressed in different tissues. Hence, tissue-specific coregulation of maternally expressed genes might be an important feature of this domain.

Animals↗

PubMed2005

Epigenetic status of the H19 locus in human oocytes following in vitro maturation.

Imprinting is an epigenetic modification that is reprogrammed in the germ line and leads to the monoallelic expression of some genes. Imprinting involves DNA methylation. Maternal imprint is reset during oocyte growth and maturation. In vitro maturation (IVM) of oocytes may, therefore, interfere with imprint acquisition and/or maintenance. To evaluate if maturing human oocytes in vitro would be hazardous at the epigenetic level, we first determined the methylation profile of the H19 differentially methylated region (DMR). The methylation status of the H19 DMR seems particularly vulnerable to in vitro culture conditions. We analyzed oocytes at different stages of maturation following IVM, germinal vesicle (GV), metaphase I (MI), and metaphase II (MII), using the bisulfite mutagenesis technique. Our results indicated that the unmethylated specific maternal profile for the H19 DMR was stably established at the GV stage. The majority of MI-arrested oocytes exhibited an altered pattern of methylation, the CTCF-binding site being methylated in half of the DNA strands analyzed. Of the 20 MII oocytes analyzed, 15 showed the normal unmethylated maternal pattern, while 5 originating from two different patients exhibited a methylated pattern. These findings highlight the need for extended analysis on MII-rescued oocytes to appreciate the epigenetic safety of the IVM procedure, before it becomes a routine and practical assisted reproductive procedure.

Adult↗

PubMed2026

Comprehensive analysis of differentially expressed mRNAs, lncRNAs, and miRNAs involved in ovarian differentiation and development in Qihe gibel carp (Carassius gibelio var. Qihe).

Qihe gibel carp (Carassius gibelio var. Qihe) exhibits diverse reproductive modes including gynogenesis and sexual reproduction, yet the molecular mechanisms of ovarian differentiation remain poorly understood. Ovarian tissues at 20, 30, and 60 days after hatching (dah), representing key stages covering early ovarian differentiation and primary oocyte growth, were subjected to whole-transcriptome sequencing. A total of 27,259 mRNAs, 2622 lncRNAs, and 2467 miRNAs were differentially expressed. Cell cycle, transcription, translation, and DNA replication pathways were significantly upregulated from 20 to 60 dah. Oocyte meiosis was enriched from 20 and 30 dah, whereas metabolic pathways (lipid, carbohydrate, and nucleotide metabolism) were enriched from 30 to 60 dah, indicating sequential progression from meiosis initiation to primary oocyte growth with nutrient synthesis. Hub lncRNAs and key ceRNA networks (e.g., MSTRG.28669.5-miR-221-ccnb2) were identified. This study provides the first comprehensive characterization of ncRNA-mediated regulation and ceRNA networks during ovarian development in Qihe gibel carp, establishing a foundation for understanding ovarian differentiation in this species.

Animals↗

PubMed2003

Detection of oncofetal h19 RNA in rheumatoid arthritis synovial tissue.

The expression of oncofetal H19 RNA and its localization/cellular source was analyzed in synovial tissue (ST) and isolated synovial macrophages (Mphi) or synovial fibroblasts (SFBs) by reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. RT-PCR showed significantly higher H19 expression in ST from patients with rheumatoid arthritis (RA) (P = 0.000) and osteoarthritis (OA) (P = 0.009) than in normal/joint trauma controls (N/JT), but comparable levels in reactive arthritis. In situ hybridization demonstrated strong signals in all RA-ST samples (n = 8), with > or =85% positive cells in the lining layer, diffuse infiltrates, and stroma regions. In lymphoid aggregates and endothelial cells only 20% were positive. RA-ST contained a significantly higher percentage of strongly positive lining cells than OA-ST and N/JT-ST. H19 RNA was expressed in both Mphi and SFBs, as confirmed by RT-PCR in isolated RA Mphi and SFBs (n = 3). In RA-SFBs, low constitutive H19 RNA expression in culture (10% fetal calf serum) was strongly increased on starvation (3.5-fold, 1% fetal calf serum), with or without the addition of interleukin-1beta (10 to 100 U/ml), tumor necrosis factor-alpha (1 to 25 ng/ml), or platelet-derived growth factor-BB (2.5 to 10 U/ml). In OA-SFBs, this starvation-induced increase was lower (twofold), reaching significant differences compared with RA-SFBs after stimulation with interleukin-1beta and platelet-derived growth factor-BB. In both RA- and OA-SFBs, the MAP-kinase ERK-1/2 pathway and the phosphatidylinositol-3 kinase pathway influenced H19 RNA expression, as shown by inhibitor studies. Significant overexpression of H19 RNA and its increased sensitivity to starvation/cytokine regulation in RA suggests a pathogenetic role of this oncofetal gene, possibly reflecting embryonal dedifferentiation of the adult ST and/or ongoing inflammatory/oxidative stress.

Adult↗

PubMed2000

p57(KIP2) is not mutated in hepatoblastoma but shows increased transcriptional activity in a comparative analysis of the three imprinted genes p57(KIP2), IGF2, and H19.

Hepatoblastomas (HBs), representing malignant liver tumors of childhood, show frequent loss of heterozygosity (LOH) in the chromosomal region 11p15.5. This loss is of maternal origin suggesting the presence of a monoallelically expressed tumor suppressor gene in this region. p57(KIP2) (KIP2) located at 11p15.5 is predominantly expressed from the maternal allele and encodes a cyclin-dependent kinase inhibitor. We screened a series of 56 HB tumors and five HB cell lines for allelic loss (LOH) of the KIP2 locus by microsatellite analysis and KIP2 coding sequence mutations by single-strand conformation polymorphism analysis. Although LOH at the KIP2 locus occurred in 25% of the cases, no mutations were found. Analysis of KIP2 mRNA expression by competitive reverse transcriptase-polymerase chain reaction revealed up-regulation in nine of 12 HBs compared to matching liver samples. In contrast, mRNA levels of the putative suppressor gene H19 on 11p15.5 were decreased in 10 of 12 tumors, indicating that KIP2 and H19 are not co-regulated in HBs. IGF2 mRNA expression was increased in 11 of 12 HB samples. All HBs showed monoallelic KIP2 expression. However, the overexpression of KIP2 in HBs with maternal loss of 11p15.5 suggests a reactivation of the paternal allele in these cases. Overexpression of KIP2 in HBs argues against a role as a HB suppressor gene.

Child, Preschool↗

PubMed2001

Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11.

Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.

ATP-Binding Cassette Transporters↗

PubMed1998

Telomerase activity and expression of telomerase RNA component and telomerase catalytic subunit gene in cervical cancer.

Telomerase, a ribonucleoprotein complex that includes the telomerase RNA component (hTR) and the telomerase catalytic subunit gene (hTERT) product, has been shown to be activated in the majority of cancer tissues and immortalized cells. To study telomerase activation during the progression of cervical cancer, the expression of hTR and hTERT RNAs in tissues of various stages of cervical cancer was analyzed using the in situ hybridization method and compared with proliferative activity as estimated by Ki-67 immunostaining. To test whether expression of these components is reflected in enzyme activity, we determined the levels of the RNAs in cervical cancer and normal tissues and in primary and immortal keratinocytes by reverse transcription-polymerase chain reaction and RNase protection assays and compared the results to telomerase activities as detected by telomeric repeat amplification protocol assay. In situ hybridization signals of hTR and hTERT were present not only in carcinoma tissues but also in normal epidermal layers. In many adenocarcinoma and fewer squamous cell carcinoma tissues, both signals were focally increased where high proliferative activity was present at the stages of dysplasia/metaplasia, in situ carcinoma, and invasive carcinoma. The level of bTERT, as quantitated by RNase protection assay, was not different between cancer and control tissues or immortal and a subset of primary keratinocytes and did not correlate with telomerase activity. These results indicate that expression of hTR and bTERT is up-regulated in at least a subset of neoplastic cells at an early stage of carcinogenesis and that unidentified factors, such as the modulation or coordination of its protein level with other products, may contribute to the activation of telomerase in cervical cancer.

Cell Division↗