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At least 631 records · Page 35Linked to original sources
PubMed2004

Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation.

Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner. We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF. Chromatin immunoprecipitation-on-chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions.

Animals↗
PubMed2005

Epigenetic status of human embryonic stem cells.

We examined the allele-specific expression of six imprinted genes and the methylation profiles of three imprinting control regions to assess the epigenetic status of human embryonic stem cells. We identified generally monoallelic gene expression and normal methylation patterns. During prolonged passage, one cell line became biallelic with respect to H19, but without loss of the gametic methylation imprint. These data argue for a substantial degree of epigenetic stability in human embryonic stem cells.

Alleles↗
PubMed2005

Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome.

Silver-Russell syndrome (SRS, OMIM 180860) is a congenital disorder characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features and body asymmetry. SRS is genetically heterogenous with maternal uniparental disomy with respect to chromosome 7 occurring in approximately 10% of affected individuals. Given the crucial role of the 11p15 imprinted region in the control of fetal growth, we hypothesized that dysregulation of genes at 11p15 might be involved in syndromic intrauterine growth retardation. We identified an epimutation (demethylation) in the telomeric imprinting center region ICR1 of the 11p15 region in several individuals with clinically typical SRS. This epigenetic defect is associated with, and probably responsible for, relaxation of imprinting and biallelic expression of H19 and downregulation of IGF2. These findings provide new insight into the pathogenesis of SRS and strongly suggest that the 11p15 imprinted region, in addition to those of 7p11.2-p13 and 7q31-qter, is involved in SRS.

CCCTC-Binding Factor↗
PubMed2006

Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions.

Accumulating evidence converges on the possibility that chromosomes interact with each other to regulate transcription in trans. To systematically explore the epigenetic dimension of such interactions, we devised a strategy termed circular chromosome conformation capture (4C). This approach involves a circularization step that enables high-throughput screening of physical interactions between chromosomes without a preconceived idea of the interacting partners. Here we identify 114 unique sequences from all autosomes, several of which interact primarily with the maternally inherited H19 imprinting control region. Imprinted domains were strongly overrepresented in the library of 4C sequences, further highlighting the epigenetic nature of these interactions. Moreover, we found that the direct interaction between differentially methylated regions was linked to epigenetic regulation of transcription in trans. Finally, the patterns of interactions specific to the maternal H19 imprinting control region underwent reprogramming during in vitro maturation of embryonic stem cells. These observations shed new light on development, cancer epigenetics and the evolution of imprinting.

Animals↗
PubMed2002

Aberrant patterns of X chromosome inactivation in bovine clones.

In mammals, epigenetic marks on the X chromosomes are involved in dosage compensation. Specifically, they are required for X chromosome inactivation (XCI), the random transcriptional silencing of one of the two X chromosomes in female cells during late blastocyst development. During natural reproduction, both X chromosomes are active in the female zygote. In somatic-cell cloning, however, the cloned embryos receive one active (Xa) and one inactive (Xi) X chromosome from the donor cells. Patterns of XCIhave been reported normal in cloned mice, but have yet to be investigated in other species. We examined allele-specific expression of the X-linked monoamine oxidase type A (MAOA) gene and the expression of nine additional X-linked genes in nine cloned XX calves. We found aberrant expression patterns in nine of ten X-linked genes and hypomethylation of Xist in organs of deceased clones. Analysis of MAOA expression in bovine placentae from natural reproduction revealed imprinted XCI with preferential inactivation of the paternal X chromosome. In contrast, we found random XCI in placentae of the deceased clones but completely skewed XCI in that of live clones. Thus, incomplete nuclear reprogramming may generate abnormal epigenetic marks on the X chromosomes of cloned cattle, affecting both random and imprinted XCI.

Animals↗
PubMed2002

Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation.

Tsix controls X-chromosome inactivation (XCI) by blocking the accumulation of Xist RNA on the future active X chromosome. Deleting Tsix on one X chromosome (X(Delta)X) skews XCI toward the mutated X chromosome in the female soma. Here I have generated homozygous Tsix-null mice (X(Delta)X(Delta)) to test how deleting the second allele affects the choice of XCI. Homozygosity leads to extremely low fertility and reveals two previously unknown non-mendelian patterns of inheritance. First, the sex ratio is skewed against female births so that one daughter is born for every two to three sons. Second, the pattern of XCI unexpectedly returns to random in surviving X(Delta)X(Delta) mice. Thus, with respect to choice, mutation of Tsix yields a phenotypic abnormality in heterozygotes but not homozygotes. To reconcile the paradox of female loss with apparent reversion to random choice, I propose that deleting both Tsix alleles results in chaotic choice and that randomness in X(Delta)X(Delta) survivors reflects a fortuitous selection of distinct X chromosomes as active and inactive.

Animals↗
PubMed1996

Somatic overgrowth associated with overexpression of insulin-like growth factor II.

Overexpression of the normally imprinted fetal insulin-like growth factor II (IGF2) has been implicated in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). We have detected constitutional relaxation of imprinting of IGF2 in four children with somatic overgrowth who do not show diagnostic features of BWS. Three children showed constitutional abnormalities of H19 methylation. All four children showed nephromegaly and two developed Wilms' tumors. Gene methylation is known to be associated with gene silencing, and three children showed constitutional abnormalities of H19 gene methylation. Disruption of H19 methylation, and concomitant relaxation of IGF2 imprinting, provides another mechanism that can increase IGF2 expression in children with overgrowth. The accumulated data on normal and pathologic IGF2 expression are now sufficient to define an entity, "IGF2 overgrowth disorder," of which BWS may be one extreme manifestation. These findings have broad implications for the characterization of idiopathic overgrowth.

Base Sequence↗
PubMed2006

Telomerase therapeutics for cancer: challenges and new directions.

It has been approximately a decade since telomerase was described as an almost universal marker for human cancer. Most human tumours not only express telomerase but also have very short telomeres, whereas telomerase activity is either reduced or absent in normal tissues, making the inhibition of telomerase an attractive target for cancer therapeutics. Here we review the current status of telomerase therapeutics and discuss future opportunities and challenges for telomerase research, including a possible relationship with cancer stem cells that could be a source of chemo-/radioresistance development in many advanced cancers.

Animals↗
PubMed2025

Expression regulation network in papillae of sea cucumbers: Whole-transcriptome and DNA methylation datasets.

To elucidate the expression regulation network of papilla size of sea cucumbers (Apostichopus japonicus), the whole-transcriptome and DNA methylome datasets of different sizes of papillae in sea cucumbers were generated. Average clean bases of whole-transcriptome (16.35 G) and DNA methylome (28.92 G) were obtained using RNA sequencing and whole-genome bisulfite sequencing techniques. A total of 3,188 ceRNA networks were also identified including 3,081 long non-coding RNAs (lncRNA)/microRNAs (miRNA)/mRNA networks and 107 circular RNA (circRNA)/miRNA/mRNA networks. Methylome data indicate that there were 3,307 and 3,776 differentially methylated regions (DMRs) with high-level methylation as well as 3,125 and 3,016 DMRs with low-level methylation in big papillae compared to small papillae. The identified DMRs were mainly distributed in introns, promotors, or exons. The whole-transcriptome and DNA methylome datasets generated from this study not only established a robust theoretical foundation (especially from the epigenetic aspect) for elucidating expression regulation network determining papilla size in sea cucumbers but also can be a valuable resource of biomarker mining for papilla appearance-based selective breeding in sea cucumbers.

DNA Methylation↗
PubMed2002

Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer.

This study addresses the hypothesis that altered expression of oestrogen receptor-beta and/or altered relative expression of coactivators and corepressors of oestrogen receptors are associated with and may be mechanisms of de novo tamoxifen resistance in oestrogen receptor positive breast cancer. All cases were oestrogen receptor +, node negative, primary breast tumours from patients who later had no disease progression (tamoxifen sensitive) or whose disease progressed while on tamoxifen (tamoxifen resistant). Using an antibody to oestrogen receptor-beta that detects multiple forms of this protein (total) but not an antibody that detects only full-length oestrogen receptor-beta 1, it was found that high total oestrogen receptor beta protein expressors were more frequently observed in tamoxifen sensitive tumours than resistant tumours (Fisher's exact test, P=0.046). However, no significant differences in the relative expression of oestrogen receptor beta2, oestrogen receptor beta5 and full-length oestrogen receptor beta1 RNA in the tamoxifen sensitive and resistant groups were found. Also, when the relative expression of two known coactivators, steroid receptor RNA activator and amplified in breast cancer 1 RNA to the known corepressor, repressor of oestrogen receptor activity RNA, was examined, no significant differences between the tamoxifen sensitive and resistant groups were found. Altogether, there is little evidence for altered coregulators expression in breast tumours that are de novo tamoxifen resistant. However, our data provide preliminary evidence that the expression of oestrogen receptor beta protein isoforms may differ in primary tumours of breast cancer patients who prove to have differential sensitivity to tamoxifen therapy.

Antineoplastic Agents, Hormonal↗
PubMed2001

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental abnormalities, tissue and organ hyperplasia and an increased risk of embryonal tumours (most commonly Wilms tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. Molecular diagnosis of BWS is currently difficult, mostly due to the large spectrum of genetic and epigenetic abnormalities. The other difficulty in managing BWS is the identification of patients at risk of tumour. An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele. A loss of imprinting of the KCNQ1OT gene, associated with the loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 has been described in BWS patients. The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS. The allelic status of the 11p15 region and the methylation status of the KCNQ1OT and H19 genes were investigated in leukocyte DNA from 97 patients referred for BWS and classified into two groups according to clinical data: complete BWS (CBWS) (n=61) and incomplete BWS (IBWS) (n=36). Fifty-eight (60%) patients (39/61 CBWS and 19/36 IBWS) displayed abnormal demethylation of KvDMR1. In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS). Thirteen of the 39 patients with normal methylation of KvDMR1 displayed hypermethylation of the H19 gene. These 13 patients included two siblings with 11p15 trisomy. These results show that analysis of the methylation status of KvDMR1 and the H19 gene in leukocyte DNA is useful in the diagnosis of 11p15-related overgrowth syndromes, resulting in the diagnosis of BWS in more than 70% of investigated patients. We also evaluated clinical and molecular features as prognostic factors for tumour and showed that mosaicism for 11p15 UPD and hypermethylation of the H19 gene in blood cells were associated with an increased risk of tumour.

Adolescent↗
PubMed2002

Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay.

A 46,X,r(X) karyotype was found in a three and a half year old girl with short stature, facial dysmorphism and developmental delay. The clinical findings were consistent with the phenotype described in a limited number of patients with small ring X chromosomes lacking the XIST locus, a critical player in the process of X chromosome inactivation. Surprisingly, in our patient, fluorescent in situ hybridisation demonstrated that the XIST locus was present on the ring X. However, expression studies showed that there was no XIST transcript in peripheral blood cells, suggesting that the ring X had not been inactivated. This was confirmed by the demonstration that both of the patient's alleles for the androgen receptor gene were unmethylated, and that both of the patient's ZXDA alleles were expressed. The active nature of the ring X would presumably result in overexpression of genes that may account for the developmental delay observed for the patient. Using polymorphic markers along the X chromosome, the ring X was determined to be of paternal origin with one breakpoint in the long arm between DXS8037 and XIST and one in the short arm in Xp11.2 between DXS1126 and DXS991. To attempt to determine why the XIST gene failed to be expressed, the promoter region was sequenced and found to have a base change at the same location as a variant previously associated with nonrandom X chromosome inactivation. This mutation was not seen in over one hundred normal X chromosomes examined; however, it was observed in the paternal grandmother who did not show substantial skewing of X chromosome inactivation.

Abnormalities, Multiple↗
PubMed2003

In vitro follicular growth affects oocyte imprinting establishment in mice.

In vitro folliculogenesis of cryopreserved ovarian tissue could be an effective method for insuring fertility for patients who receive gonadotoxic treatment. Although several culture systems have been described for growing female gametes in vitro, the production of competent oocytes for further development remains a considerable challenge. The purpose of our study was to determine whether maternal primary imprinting progresses normally during mouse oocyte growth in vitro. We analysed the DNA methylation status of differentially methylated regions of the imprinted genes H19, Mest/Peg1 and Igf2R using fully grown germinal vesicle-stage oocytes (fg oocytes) produced by in vitro folliculogenesis from early preantral follicles. When compared to fg oocytes removal from control females, we observed after in vitro development, a loss of methylation at the Igf2R locus in six out of seven independent experiments and Mest/Peg1 locus (one out of seven), and a gain of methylation at the H19 locus (one out of seven). These results provide insight into the dysregulation of the process of primary imprinting during oocyte growth in vitro and highlight the need for effective new biomarkers to identify complete nuclear reprogramming competence after in vitro folliculogenesis.

Animals↗
PubMed2005

Patients with familial biparental hydatidiform moles have normal methylation at imprinted genes.

In molar tissues from patients with recurrent biparental hydatidiform moles, we could previously demonstrate that differentially methylated regions (DMRs) of four imprinted genes are abnormally methylated on the maternal alleles. It remained unclear if this abnormal methylation originated de novo in the molar tissues or if it is even recognizable in the patient somatic tissues. To address this question, we investigated the DNA methylation of four imprinted genes in total blood from the two sister-patients. Here, we show that both patients retain normal methylation levels at the DMRs of the four genes in blood tissues. For two maternally expressed genes, we could use informative SNPs to follow the inheritance of the abnormally methylated maternal alleles in the molar tissues. We find that the transmitted abnormally methylated maternal alleles to the moles originated from the maternal grandmother and that the same alleles are not methylated in the patients. Our data suggest that the abnormal methylation in familial biparental molar tissues was acquired de novo in the patients'germline as a result of a false reprogramming or during the postzygotic development of the conceptuses that led to moles.

Alleles↗
PubMed2005

Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A.

A basic tenet of the Lyon hypothesis is that X inactivation occurs randomly with respect to parental origin of the X chromosome. Yet, nonrandom patterns of X inactivation are common - often ascertained in women who manifest recessive X-linked disorders despite being heterozygous for the mutation. Usually, the cause of skewing is cell selection disfavouring one of the cell lineages created by random X inactivation. We have identified a three generation kindred, with three females who have haemophilia A because of extreme skewing of X inactivation. Although they have both normal and mutant factor VIII (FVIII) alleles, only the mutant one is transcribed; and, they share an XIST allele that is never transcribed. The skewing in this case seems to result from an abnormality in the initial choice process, which prevents the chromosome bearing the mutant FVIII allele from being an inactive X.

Adult↗