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PubMed2005

A genetic approach to cancer epigenetics.

In over 20 years since the discovery of altered methylation in cancer, many epigenetic alterations have been found in human cancer, including global and specific gene hypomethylation, hypermethylation, altered chromatin marks, and loss of genomic imprinting. Cancer epigenetics has been limited by questions of cause and effect, since epigenetic changes can arise secondary to the cancer process and its associated widespread changes in gene expression. Furthermore, mutations in the DNA methylation machinery have not been observed in tumors, whereas they have been for chromatin modification. To address the issue of human cancer etiology, we have taken a genetic approach to cancer epigenetics. One line of investigation has been on the disorder Beckwith-Wiedemann syndrome (BWS). We have found that loss of imprinting (LOI) of the autocrine growth factor gene IGF2 and of the untranslated antisense RNA LIT1, within the K(V)LQT1 gene, account for most cases of BWS, and that cancer risk is specifically associated with LOI of IGF2. Wilms' tumors, both in BWS and in the general population, involve LOI leading to an expansion of nephrogenic precursor cells. We have also developed an animal model for the role of LOI of IGF2 in cancer, showing that it cooperates with Apc mutations to increase cancer frequency, consistent with human data suggesting a severalfold increased cancer risk for this common epigenetic variant in the adult population. These data suggest that a major component of cancer risk involves epigenetic changes in normal cells that increase the probability of cancer after genetic mutation. They suggest a model of cancer prevention that involves the epigenetic analysis of normal cells for risk stratification and cancer prevention strategies.

Animals↗
PubMed1998

Studying early nodulin gene ENOD40 expression and induction by nodulation factor and cytokinin in transgenic alfalfa.

ENOD40, an early nodulin gene, is expressed following inoculation with Rhizobium meliloti or by adding R. meliloti-produced nodulation (Nod) factors or the plant hormone cytokinin to uninoculated roots. We isolated two MsENOD40 clones, designated MsENOD40-1 and MsENOD40-2, with distinct promoters from an alfalfa (Medicago sativa cv Chief) genomic library. The promoters were fused to the reporter gene uidA (gus), and the constructs were introduced into alfalfa. We observed that the MsENOD40-1 construct was expressed almost exclusively under symbiotic conditions. The MsENOD40-2 construct was transcribed under both symbiotic and nonsymbiotic conditions and in nonnodular and nodular tissues. Both MsENOD40 promoter-gus constructs were similarly expressed as nodules developed, and both were expressed in roots treated with 6-benzylaminopurine or purified Nod factor. However, no blue color was detected in nodule-like structures induced by the auxin transport inhibitor N-1-(naphthyl)phthalamic acid on roots of plants containing the MsENOD40-1 promoter construct, whereas pseudonodules from plants containing the MsENOD40-2 promoter construct stained blue. A 616-bp region at the distal 5' end of the promoter is important for proper spatial expression of MsENOD40 in nodules and also for Nod-factor and cytokinin-induced expression.

Bacterial Proteins↗
PubMed2004

Enod40, a short open reading frame-containing mRNA, induces cytoplasmic localization of a nuclear RNA binding protein in Medicago truncatula.

In eukaryotes, diverse mRNAs containing only short open reading frames (sORF-mRNAs) are induced at specific stages of development. Their mechanisms of action may involve the RNA itself and/or sORF-encoded oligopeptides. Enod40 genes code for highly structured plant sORF-mRNAs involved in root nodule organogenesis. A novel RNA binding protein interacting with the enod40 RNA, MtRBP1 (for Medicago truncatula RNA Binding Protein 1), was identified using a yeast three-hybrid screening. Immunolocalization studies and use of a MtRBP1-DsRed2 fluorescent protein fusion showed that MtRBP1 localized to nuclear speckles in plant cells but was exported into the cytoplasm during nodule development in enod40-expressing cells. Direct involvement of the enod40 RNA in MtRBP1 relocalization into cytoplasmic granules was shown using a transient expression assay. Using a (green fluorescent protein)/MS2 bacteriophage system to tag the enod40 RNA, we detected in vivo colocalization of the enod40 RNA and MtRBP1 in these granules. This in vivo approach to monitor RNA-protein interactions allowed us to demonstrate that cytoplasmic relocalization of nuclear proteins is an RNA-mediated cellular function of a sORF-mRNA.

Amino Acid Sequence↗
PubMed2004

Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease.

DNA tests in normal subjects and patients with ataxia and Parkinson's disease (PD) were carried out to assess the frequency of spinocerebellar ataxia (SCA) and to document the distribution of SCA mutations underlying ethnic Chinese in Taiwan. MJD/SCA3 (46%) was the most common autosomal dominant SCA in the Taiwanese cohort, followed by SCA6 (18%) and SCA1 (3%). No expansions of SCA types 2, 10, 12, or dentatorubropallidoluysian atrophy (DRPLA) were detected. The clinical phenotypes of these affected SCA patients were very heterogeneous. All of them showed clinical symptoms of cerebellar ataxia, with or without other associated features. The frequencies of large normal alleles are closely associated with the prevalence of SCA1, SCA2, MJD/SCA3, SCA6, and DRPLA among Taiwanese, Japanese, and Caucasians. Interestingly, abnormal expansions of SCA8 and SCA17 genes were detected in patients with PD. The clinical presentation for these patients is typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. This study appears to be the first report describing the PD phenotype in association with an expanded allele in the TATA-binding protein gene and suggests that SCA8 may also be a cause of typical PD.

Age of Onset↗
PubMed2006

CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia.

OBJECTIVES: Chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. IgV(H) mutational status, chromosomal aberrations, CD38 expression and ZAP-70 expression are prognostic markers in CLL, however, they are not exclusively confined to this disease. We recently identified a novel CLL-specific gene (CLL upregulated gene1, CLLU1) that is exclusively upregulated in CLL cells. Here we describe our evaluation of the prognostic significance of CLLU1 in CLL. METHODS: A cohort of 59 previously untreated CLL patients was studied. We determined the expression levels of two CLLU1 transcripts, cDNA1 and CDS, by quantitative RT-PCR. The relation between CLLU1 expression and time to therapy, overall survival and presence or absence of ZAP-70, CD38, chromosomal aberrations or IgV(H) mutations in the 59 patients was analyzed. RESULTS: Analyzed as a continuous, quantitative parameter CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P < or = 0.0003) Analyzed as a categorical parameter, by segregation of the patients into groups with cDNA1 or CDS expression above or below the median, the CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P = 0.001) and predicted overall survival with borderline significance (P < or = 0.05). Patient stratification according to clinical stage, cytogenetics, IgV(H) mutational status, ZAP-70 and CD38, demonstrated significantly increased CLLU1 expression in all investigated CLL poor risk groups. CLLU1 expression levels contributed additional prognostic information to ZAP-70-positive patients. CONCLUSIONS: CLLU1 is the first identified CLL specific gene. The CLLU1 mRNA expression level can predict time to initiation of treatment and survival in CLL patients.

ADP-ribosyl Cyclase 1↗
PubMedDate not supplied

H19 and IGF2 gene expression in human normal, hyperplastic, and malignant endometrium.

We examined H19 and insulin-like growth factor 2 (IGF2) gene expression in normal endometrium (12 cases), hyperplasia (27 cases), and cancer (27 cases) by non-radioactive in situ hybridization. H19 was not expressed in the epithelium of normal endometrium, but its frequency of expression was 15% in hyperplastic and 60% in neoplastic epithelium. In stroma cells, H19 frequency of expression was 75% in normal endometrium, 55% in hyperplasia, and 37% in carcinoma. According to the grade of endometrial cancer cell differentiation, H19 showed increased frequency and level of expression in the epithelium from well to moderately and poorly differentiated tissues. Our results indicate that H19 expression in epithelial cells of endometrial hyperplasia and cancer merits further investigation and could be useful as a complementary histopathologic and prognostic marker among other modalities in endometrial cancer. IGF2 expression did not appear useful for diagnostic or prognostic purposes.

Case-Control Studies↗
PubMed1996

Equivalent parental distribution of frequently lost alleles and biallelic expression of the H19 gene in human testicular germ cell tumors.

Epigenetic alterations such as genomic imprinting might play an important role in human tumorigenesis, in addition to specific genetic alterations. To clarify the role of genetic and/or epigenetic alterations in the tumorigenesis of testicular germ cell tumors (GCTs), we analyzed 40 primary and 3 metastatic testicular GCTs with regard to specific chromosomal losses and their parental origin. A high incidence of loss of heterozygosity (LOH) was demonstrated on chromosomes 1p, 3p, 11p, and 17p: 9/19 (47%), 18/39 (46%), 13/40 (33%) and 20/36 (56%), respectively. However, there was no correlation between the frequency of LOH on any chromosome and clinicopathological features. Regarding the parental origin of the lost allele at these chromosomes, preferential loss was not demonstrated in this study. To clarify the imprinting status in GCTs, we analyzed the allele-specific expression of the H19 gene, which is paternally imprinted on chromosome 11p. All of 11 tumors without LOH at this locus showed biallelic expression of H19. Based on previous work demonstrating the biallelic expression of H19 in primordial germ cells and spermatogonia in the mouse germ line, these results suggest that the biallelic expression of H19 in testicular GCTs reflects the characteristics of the original germ cells in which the imprinting marking has been erased and not established, rather than loss of imprinting during tumorigenesis. It is also possible that a failure to re-establish the imprinting might be an initial event which leads to testicular GCTs.

Alleles↗
PubMed2006

Expression profile of LIT1/KCNQ1OT1 and epigenetic status at the KvDMR1 in colorectal cancers.

The human chromosome region 11p15.5 contains a number of maternally and paternally imprinted genes, and the LIT1/KCNQ1OT1 locus acts as an imprinting center in the proximal domain of 11p15.5. Loss of imprinting (LOI) of LIT1 and its correlation with methylation status at a differentially methylated region, the KvDMR1, were investigated in 69 colorectal cancer tissue specimens. LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines. In 69 colorectal cancer tissue specimens, LOI of LIT1 was observed in nine of the 17 (53%) informative cases. Moreover, LOI of LIT1 was only observed in tumor samples. In the cell lines, methylation status at the KvDMR1 correlated well with LIT1 expression profiles. Loss of expression of LIT1 also correlated with enrichment of H3 lysine 9 (H3-K9) dimethylation and reduction of H3 lysine 4 (H3-K4) dimethylation. Thus, LIT1 expression appears to be controlled by epigenetic modifications at the KvDMR1, although CDKN1C expression, which is considered to be controlled by LIT1, was not associated with epigenetic status at the KvDMR1 in some colorectal cancer cell lines. Therefore, these findings suggest that LOI of LIT1 via epigenetic disruption plays an important role in colorectal carcinogenesis, but it is not necessarily associated with CDKN1C expression.

Chromatin Immunoprecipitation↗
PubMed2005

CsrA and three redundant small RNAs regulate quorum sensing in Vibrio cholerae.

Bacteria communicate using a process called quorum sensing which involves production, secretion and detection of signalling molecules called autoinducers. Quorum sensing allows populations of bacteria to simultaneously regulate gene expression in response to changes in cell density. The human pathogen, Vibrio cholerae, uses a quorum-sensing circuit composed of parallel systems that transduce information through four redundant regulatory small RNAs (sRNAs) called quorum regulatory RNAs (Qrr) to control the expression of numerous genes, most notably those required for virulence. We show that the VarS/VarA two-component sensory system comprises an additional regulatory input controlling quorum-sensing-dependent gene expression in V. cholerae. VarS/VarA controls transcription of three previously unidentified small regulatory RNAs (sRNAs) that are similar to the sRNAs CsrB and CsrC of Escherichia coli. The three V. cholerae sRNAs, which we name CsrB, CsrC and CsrD, act redundantly to control the activity of the global regulatory protein, CsrA. The VarS/VarA-CsrA/BCD system converges with the V. cholerae quorum-sensing systems to regulate the expression of the Qrr sRNAs, and thus, the entire quorum-sensing regulon.

Adaptation, Physiological↗
PubMed2005

De-differentiation-derived mesenchymal stem cells demonstrate selective repression in H19 bioregulatory RNA gene expression.

Cellular de-differentiation can induce anticancer activity that makes cells resistant to carcinogenesis, but the molecular mechanism of this phenomenon has not been defined. To determine whether stable molecular changes develop in association with the process of de-differentiation, DNA microarray analyses were performed. These analyses compared control undifferentiated cells with three carcinogenesis-resistant clones of de-differentiated cells that were derived from mature adipocytes. The results of analysis of 6,000 genes and 6,000 ESTs establish that relative to control cells, all three de-differentiation-derived cell clones demonstrate that only one gene shows a consistent difference in expression. The expression of the H19 bioregulatory RNA is repressed an average of >fourfold in all de-differentiated cell clones. Real-time PCR analyses confirm these findings. This suggests that decreased H19 expression may account, at least in part, for the anticancer activity observed in de-differentiated cell clones.

Animals↗
PubMedDate not supplied

Klinefelter's syndrome: new and rapid diagnosis by PCR analysis of XIST gene expression.

Diagnosis of Klinefelter's syndrome relies on raised gonadotropin levels in serum, azoospermia, determination of sex chromatin in oral swabs and finally chromosome analysis in leukocyte cell culture. By this method the numerical chromosome aberration with a 47, XXY karyotype can be detected. However, diagnosis can be accelerated by demonstration of RNA expression of an X-linked gene, which serves as a marker for inactivation of the second and any further extra X chromosome in the cell. This so-called X-inactive-specific transcript (XIST) is transcribed exclusively from the inactive X chromosome. RNA was isolated both from Ficoll-prepared peripheral blood leukocytes and from total EDTA blood of Klinefelter patients and control persons. RNA was reverse transcribed and finally detected by the polymerase chain reaction (PCR) with XIST-specific sequences. The pyruvate dehydrogenase gene was used as a control gene for successful RNA preparation and reverse transcription. XIST transcripts could be detected in all blood samples from Klinefelter patients (n = 15, karyotype 47, XXY) and female persons (n = 3). Fertile men (n = 5) were negative for this transcript in peripheral blood. Thus, diagnosis of Klinefelter's syndrome can be accelerated without loss of sensitivity and specificity by detection of XIST expression in peripheral blood leukocytes.

Adult↗
PubMed2006

Refined association mapping for a quantitative trait: weight in the H19-IGF2-INS-TH region.

Previous analyses have provided evidence for one or more loci affecting body weight in the H19-IGF2-INS-TH region on chromosome 11p15. To identify the location of a possible causal locus or loci we applied association analysis by composite likelihood to a large cohort under the Malecot model for body weight. A random sample of 2731 men in the UK were typed for eleven single nucleotide polymorphisms (SNPs) in IGF2, two SNPs in H19, one SNP in INS and one microsatellite marker in the TH genes. Using F tests appropriate to small marker sets, the superiority of regression over correlation was confirmed. All the evidence for association came from IGF2, with P= 0.007 for height-adjusted weight and P= 0.019 for weight additionally adjusted for smoking and alcohol drinking. Although the estimated point location for the suspected causal variant was close to IGF2 ApaI, the 95% confidence and support intervals covered most of IGF2 but none of the other loci. Identification of the causal SNP or SNPs within IGF2 will require typing of more variants in this region.

Body Mass Index↗
PubMed1997

Duplication and polymorphism in the MHC: Alu generated diversity and polymorphism within the PERB11 gene family.

The PERB11 gene family has at least five members within the telomeric region of the MHC. The PERB11.1 and PERB11.2 genes are approximately 40 kb and 160 kb centromeric of HLA-B, respectively. Using continuous genomic sequence encompassing PERB11.1 and PERB11.2, we have found a large (approximately 25 kb) segmental duplication extending beyond the genes themselves and other potential coding sequences. The major difference between the segments are large indels which are predominantly Alu sequences. The Alu sequences within the duplicated segments have created diversity via the internal and 3' poly A-rich region. A sequence comparison of an Alu sequence between two different human ancestral haplotypes shows a high level of polymorphism, particularly in the poly A-rich regions. This study characterises the Alu sequences within the peri-PERB11.1 and peri-PERB11.2 duplicated segments in relation to diversity and polymorphism and as evolutionary markers.

Base Sequence↗
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↗
PubMed2003

Role of histone H3 lysine 27 methylation in X inactivation.

The Polycomb group (PcG) protein Eed is implicated in regulation of imprinted X-chromosome inactivation in extraembryonic cells but not of random X inactivation in embryonic cells. The Drosophila homolog of the Eed-Ezh2 PcG protein complex achieves gene silencing through methylation of histone H3 on lysine 27 (H3-K27), which suggests a role for H3-K27 methylation in imprinted X inactivation. Here we demonstrate that transient recruitment of the Eed-Ezh2 complex to the inactive X chromosome (Xi) occurs during initiation of X inactivation in both extraembryonic and embryonic cells and is accompanied by H3-K27 methylation. Recruitment of the complex and methylation on the Xi depend on Xist RNA but are independent of its silencing function. Together, our results suggest a role for Eed-Ezh2-mediated H3-K27 methylation during initiation of both imprinted and random X inactivation and demonstrate that H3-K27 methylation is not sufficient for silencing of the Xi.

Animals↗
PubMed2004

Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.

The imprinted regulation of H19 and Insulin-like growth factor 2 expression involves binding of the vertebrate insulator protein, CCCTC binding factor (CTCF), to the maternally hypomethylated differentially methylated domain (DMD). How this hypomethylated state is maintained during oogenesis and the role of CTCF, if any, in this process are not understood. With the use of a transgenic RNA interference (RNAi)-based approach to generate oocytes with reduced amounts of CTCF protein, we found increased methylation of the H19 DMD and decreased developmental competence of CTCF-deficient oocytes. Our results suggest that CTCF protects the H19 DMD from de novo methylation during oocyte growth and is required for normal preimplantation development.

Actins↗
PubMed2004

Reactivation of the paternal X chromosome in early mouse embryos.

It is generally accepted that paternally imprinted X inactivation occurs exclusively in extraembryonic lineages of mouse embryos, whereas cells of the embryo proper, derived from the inner cell mass (ICM), undergo only random X inactivation. Here we show that imprinted X inactivation, in fact, occurs in all cells of early embryos and that the paternal X is then selectively reactivated in cells allocated to the ICM. This contrasts with more differentiated cell types where X inactivation is highly stable and generally irreversible. Our observations illustrate that an important component of genome plasticity in early development is the capacity to reverse heritable gene silencing decisions.

Acetylation↗