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PubMed1992

The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus.

The Xist gene maps to the X inactivation center region in both mouse and human, and previous analysis of the 3' end of the gene has demonstrated inactive X-specific expression, suggesting a possible role in X inactivation. We have now analyzed the entire mouse Xist gene. The mature inactive X-specific transcript is 15 kb in length and contains no conserved ORF. The Xist sequence contains a number of regions comprised of tandem repeats. Comparison with the human XIST gene demonstrates significant conservation of sequence and gene structure. Xist RNA is not associated with the translational machinery of the cell and is located almost exclusively in the nucleus. Together with conservation of inactive X-specific expression, these findings support a role for Xist in X inactivation, possibly as a functional RNA or as a chromatin organizer region.

Animals↗
PubMed1992

The human XIST gene: analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus.

X chromosome inactivation in mammalian females results in the cis-limited transcriptional inactivity of most of the genes on one X chromosome. The XIST gene is unique among X-linked genes in being expressed exclusively from the inactive X chromosome. Human XIST cDNAs containing at least eight exons and totaling 17 kb have been isolated and sequenced within the region on the X chromosome known to contain the X inactivation center. The XIST gene includes several tandem repeats, the most 5' of which are evolutionarily conserved. The gene does not contain any significant conserved ORFs and thus does not appear to encode a protein, suggesting that XIST may function as a structural RNA within the nucleus. Consistent with this, fluorescence in situ hybridization experiments demonstrate localization of XIST RNA within the nucleus to a position indistinguishable from the X inactivation-associated Barr body.

Base Sequence↗
PubMed1994

Evidence that random and imprinted Xist expression is controlled by preemptive methylation.

The mouse Xist gene is expressed exclusively from the inactive X chromosome and may control the initiation of X inactivation. We show that in somatic tissues the 5' end of the silent Xist allele on the active X chromosome is fully methylated, while the expressed allele on the inactive X is completely unmethylated. In tissues that undergo imprinted paternal Xist expression and imprinted X inactivation, the paternal Xist allele is unmethylated, and the silent maternal allele is fully methylated. In the male germline, a developmentally regulated demethylation of Xist occurs at the onset of meiosis and is retained in mature spermatozoa. This may be the cause of imprinted expression of the paternal Xist allele. A role for methylation in the control of Xist expression is further supported by the finding that in differentiating embryonic stem cells during the initiation of X inactivation, differential methylation of Xist alleles precedes the onset of Xist expression.

Animals↗
PubMed1996

X chromosome imprinting and inactivation in the early mammalian embryo.

Quantitative differences in X-linked gene expression between androgenetic (two paternal genomes), gynogenetic (two maternal genomes) and normal embryos provide clues into the roles of genomic imprinting and the X:autosome ratio in controlling X chromosome function during development. These data and many others can be accounted for by a new model of X-chromosome-inactivation (XCI). Expression of the Xist RNA from all paternal X chromosomes during development preimplantation leads to repression of genes near the X-chromosome-inactivation center (Xic). Other genes are repressed as a result of spreading of the inactivation, but only in embryos with at least two X chromosomes. XY androgenones are only deficient in expression of genes near the Xic and can form blastocysts, whereas XX androgenones completely inactivate both X chromosomes and die before the blastocyst stage. The X:autosome ratio regulates XCI solely by promoting the spread of inactivation away from the Xic on chromosomes that express Xist. Methylation of the maternal Xist gene is retained in extraembryonic tissues, so that gynogenones and parthenogenones cannot express Xist, do not undergo XCI in those tissues, and so have extraembryonic defects. This model should be relevant to understanding how aberrant X chromosome regulation might occur and how this might contribute to distortion of the X-chromosome-transmission ratio, sex ratio distortion, and disease.

Animals↗
PubMed1995

The H19 gene is expressed within both epithelial and stromal components of human invasive adenocarcinomas.

In a previous work, we have isolated the human H19 gene and shown accumulation of transcripts in various human tumors including breast carcinomas (Douc-Rasy et al (1993) Int J Oncol 2, 753-758). Questions arose, after Northern blot results, about the precise H19 mRNA location, specially in normal breast tissues and benign or malign primary breast tumors. Then we performed molecular in situ hybridization to get insight into tissue expression of the H19 gene. Examined resections included one normal tissue, one fibroadenoma and 13 cancers. Results obtained with the H19 probe can be summarized as follows: 1) in normal breast tissues signals were focally observed in epithelial cells, but more predominantly in the palleal tissue which is sensitive to hormones; 2) in the fibroadenoma, fibroblastic cells were extensively labeled at the stroma-epithelium boundary, but epithelial cells were negative; and 3) in primary cancers, eight specimens exhibited signals on stromal cells, one specimen on epithelial cells and four on both epithelial and stromal cells. Data provide the following evidence: 1) usually labeled cells are clustered, either within normal or pathological tissues; 2) the labeling pattern highly differs from one tumor to another; and 3) H19 probe displays very different signals from one cell to another in given compartment of a given tissue section. In conclusion, it seems that a high H19 expression matches the tumor invasion. Our results suggest that the expression of this gene is concerned by the relationships between epithelial and stromal cells, and can reflect peculiar physiological states of the cells. Furthermore, we discuss results showing an abundant expression of H19 gene in some adenocarcinomas of bad prognosis, in the context of the otherwise established tumor-suppressor role of this gene, or the strictly controlled gene dosage, which could be overridden in these particular cases.

Adenocarcinoma↗
PubMed1996

Neural BC1 RNA in mouse skeletal muscle is a denervation-induced RNA whose expression is developmentally regulated.

We detected neural BC1 RNA in mouse skeletal muscle. The level of BC1 RNA was high in the fetus, but it declined progressively to the adult level as development proceeded. These observations suggest that this RNA is involved in the prenatal development and differentiation of muscles. Although its developmental expression correlates with the fetal period of polyneuronal innervation, BC1 RNA does not seem to play a direct role(s) in synaptogenesis, since its expression was not restricted to the neuromuscular junction. We also demonstrated that the BC1 RNA level in adult muscle was elevated after denervation, suggesting that changes in the activity of muscles or neural factors caused by axotomy, or both may result in BC1 RNA upregulation.

Actins↗
PubMed1995

H19 is imprinted in the choroid plexus and leptomeninges of the mouse foetus.

It has been proposed that either the Igf-2 gene or the H19 gene--but not both--can be expressed from a given chromosome. Igf-2 is known to be biallelically expressed in the choroid plexus and leptomeninges, however, raising the question of whether H19 is down-regulated or absent there. We found by in situ hybridization that H19 is indeed expressed in the choroid plexus and leptomeninges of the developing mouse foetus. Comparison with the expression pattern of Igf-2 showed that the genes are coexpressed in all areas, with the exception of the choroid plexus epithelium. To evaluate whether H19 is also biallelically expressed in these tissues, we microdissected embryos from interspecific crosses and performed RNAse protection analysis on the isolated RNA. This revealed that H19 maintains its imprint in the choroid plexus/leptomeninges, being transcribed from the maternal allele at a level comparable to that in normal liver. We discuss the significance of these results for current models of Igf-2 and H19 imprinting.

Alleles↗
PubMed2020

LINC00922 regulates epithelial-mesenchymal transition, invasive and migratory capacities in breast cancer through promoting NKD2 methylation.

Breast cancer ranks as the major reason for mortality in women populations, accounting for 23% of all cancer deaths. One in every three Asian women encounters the risk of this cancer in their lifetime. Long intergenic non-coding RNAs (lincRNAs) have emerged as tumor promoters and suppressors. The molecular mechanism of breast cancer remains elusive. Therefore, the current study aimed to explore the role lincRNA LINC00922 plays in the development of breast cancer. Breast cancer tissues and adjacent tissues were obtained from 109 patients with breast cancer. The RNA extraction and quantification and immunohistochemical staining characterized the high expression of LINC00922 and low expression of NKD2 in breast cancer tissues in comparison to its adjacent counterparts. Furthermore, the ectopic expression and knockdown experiments were conducted to figure out the in vivo and in vitro effects of LINC00922 on breast cancer progression. The ectopically expressed LINC00922 activated the Wnt signaling pathway, promoted epithelial-mesenchymal transition, cell proliferative, invasive and migratory capacities, tumor growth and metastasis. Additionally, the RIP and ChIP assay identified that LINC00922 recruited DNMT1, DNMT3A and DNMT3B proteins in the promoter region of NKD2 to promote NKD2 promoter methylation, thus reducing the NKD2 expression. Moreover, the Wnt signaling pathway was activated subsequent to NKD2 silencing, which was reversed by LINC00922 silencing. Lastly, the anti-oncogenic effects of LINC00922 inhibition was antagonized after NKD2 knocked down. The current study provides evidence that LINC00922 acts as a tumor promoter by promoting NKD2 methylation. Hopefully, it provides a novel potential gene target for the treatment of breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Conservation of IGF2-H19 and IGF2R imprinting in sheep: effects of somatic cell nuclear transfer.

In different mammalian species, in vitro culture and manipulation can lead to aberrant fetal and peri-natal development. It has been postulated that these diverse abnormalities are caused by epigenetic alterations and that these could affect genes that are regulated by genomic imprinting. To explore this hypothesis relative to somatic cell nuclear transfer in sheep, we investigated whether the ovine H19-IGF2 and IGF2R loci are imprinted and analysed their DNA methylation status in cloned lambs. A comparison between parthenogenetic and control concepti established that imprinting at these two growth-related loci is evolutionarily conserved in sheep. As in humans and mice, IGF2R and H19 comprise differentially methylated regions (DMRs) that are methylated on one of the two parental alleles predominantly. In tongue tissue from 12 out of 13 cloned lambs analysed, the DMR in the second intron of IGF2R had strongly reduced levels of DNA methylation. The DMR located upstream of the ovine H19 gene was found to be similarly organised as in humans and mice, with multiple CTCF binding sites. At this DMR, however, aberrant methylation was observed in only one of the cloned lambs. Although the underlying mechanisms remain to be determined, our data indicate that somatic cell nuclear transfer procedures can lead to epigenetic deregulation at imprinted loci.

Alleles↗
PubMed2026

Functional characterization of lncIMF_17214 in regulating intramuscular fat deposition of yellow-feathered broilers.

Intramuscular fat (IMF) content and lipid composition are key determinants of both the nutritional value and sensory attributes of poultry meat, yet the underlying regulatory mechanisms remain insufficiently elucidated. In this study, triglyceride (TG) content was employed as a quantitative phenotypic proxy to dissect the molecular basis of IMF deposition in yellow-feathered broilers. By integrating TG phenotypic data from 315 individuals with transcriptomic profiles and whole-genome resequencing datasets, a TG-associated long noncoding RNA (lncRNA), lncIMF_17214, was identified. Functional characterization revealed that lncIMF_17214 functions as a negative regulator of lipid deposition. Specifically, its knockdown led to significant increases in TG and total cholesterol concentrations, promoted lipid droplet accumulation, and decreased shear force in breast muscle, whereas its overexpression elicited the opposite effects. Mechanistically, lncIMF_17214 interacts with the RNA-binding protein CNBP, forming a regulatory complex that inhibits lipid accumulation. Furthermore, liver-directed overexpression increased the abundance of lncIMF_17214 in plasma exosomes, while liver-directed manipulation was associated with changes in hepatic and breast-muscle lipid deposition; direct exosome-mediated transfer to intramuscular adipocytes remains to be established. Transcriptomic profiling coupled with pathway enrichment analyses demonstrated that lncIMF_17214 predominantly influences steroid biosynthesis, unsaturated fatty acid metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. This suggests that it may be involved in the regulation of these pathways, although the underlying molecular mechanisms remain to be further elucidated. Collectively, these findings define a lncIMF_17214-centered regulatory axis linking intracellular and systemic lipid metabolism and provide a robust molecular framework for the targeted improvement of meat quality traits in yellow-feathered broilers.

Breast muscle↗
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↗
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↗
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↗