Epigenetic Heterogeneity at Imprinted Loci in Normal Populations

Sakatani, Takashi; Wei, Michelle; Katoh, Motonobu; Okita, Chiga; Wada, Daisuke; Mitsuya, Kohzoh; Meguro, Mitsue; Ikeguchi, Masahide; Ito, Hisao; Tycko, Benjamin; Oshimura, Mitsuo

doi:10.1006/bbrc.2001.4916

Cited by 92 publications

(51 citation statements)

References 32 publications

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“…Both showed partial relaxation of imprinting, with an allelic ratio 4:1 in line LV.EB and 5:1 in line SL.RC (Fig. 1d), consistent with a level often seen in normal human tissues (7,18). Finally, as a negative control, we examined the nonimprinted gene NAP2, by RT-PCR using a G͞A polymorphism we identified at nucleotide 2166, which is within the 3Ј UTR, and which was heterozygous in line SL.RC.…”

Section: Monoallelic Expression Of Imprinted Genes In Human Eg Cell-dsupporting

confidence: 80%

“…Three of four imprinted genes showed monoallelic expression, and the fourth, IGF2, showed partially relaxed imprinting but nevertheless at a ratio of 4:1 to 5:1, consistent with a level often seen in normal human cells (7,18). Nevertheless it may be important to ascertain IGF2 imprinting status before transplantation of a given EG-derived cell line.…”

Section: Discussionsupporting

confidence: 59%

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Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages

Onyango

Jiang

Uejima

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Imprinting is an epigenetic modification leading to monoallelic expression of some genes, and disrupted imprinting is believed to be a barrier to human stem cell transplantation, based on studies that suggest that epigenetic marks are unstable in mouse embryonic germ (EG) and embryonic stem (ES) cells. However, stem cell imprinting has not previously been examined directly in humans. We found that three imprinted genes, TSSC5, H19, and SNRPN, show monoallelic expression in in vitro differentiated human EG-derived cells, and a fourth gene, IGF2, shows partially relaxed imprinting at a ratio from 4:1 to 5:1, comparable to that found in normal somatic cells. In addition, we found normal methylation of an imprinting control region (ICR) that regulates H19 and IGF2 imprinting, suggesting that imprinting may not be a significant epigenetic barrier to human EG cell transplantation. Finally, we were able to construct an in vitro mouse model of genomic imprinting, by generating EG cells from 8.5-day embryos of an interspecific cross, in which undifferentiated cells show biallelic expression and acquire preferential parental allele expression after differentiation. This model should allow experimental manipulation of epigenetic modifications of cultured EG cells that may not be possible in human stem cell studies.

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Section: Monoallelic Expression Of Imprinted Genes In Human Eg Cell-dsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 59%

Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages

Onyango

Jiang

Uejima

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…An alternative hypothesis to explain our findings would be the occurrence of epigenetic alterations as a polymorphic characteristic in the population. Previous studies have shown that the functional imprinting of the IGF2 and H19 genes is heterogeneous and polymorphic in blood cells from normal individuals (39,40). More recently, Sandovici et al (41) observed a familial clustering of individuals with abnormal methylation ratios at H19-DMR and reported that this trait was stable over nearly two decades.…”

Section: Discussionmentioning

confidence: 99%

H19-DMR allele-specific methylation analysis reveals epigenetic heterogeneity of CTCF binding site 6 but not of site 5 in head-and-neck carcinomas: A pilot case-control analysis

et al. 2006

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Abstract. Aberrant methylation of seven potential binding sites of the CTCF factor in the differentially methylated region upstream of the H19 gene (H19-DMR) has been suggested as critical for the regulation of IGF2 and H19 imprinted genes. In this study, we analyzed the allele-specific methylation pattern of CTCF binding sites 5 and 6 using methylationsensitive restriction enzyme PCR followed by RFLP analysis in matched tumoral and lymphocyte DNA from head-andneck squamous cell carcinoma (HNSCC) patients, as well as in lymphocyte DNA from control individuals who were cancerfree. The monoallelic methylation pattern was maintained in CTCF binding site 5 in 22 heterozygous out of 91 samples analyzed. Nevertheless, a biallelic methylation pattern was detected in CTCF binding site 6 in a subgroup of HNSCC patients as a somatic acquired feature of tumor cells. An atypical biallelic methylation was also observed in both tumor and lymphocyte DNA from two patients, and at a high frequency in the control group (29 out of 64 informative controls). Additionally, we found that the C/T transition detected by HhaI RFLP suppressed one dinucleotide CpG in critical CTCF binding site 6, of a mutation showing polymorphic frequencies. Although a heterogeneous methylation pattern was observed after DNA sequencing modified by sodium bisulfite, the biallelic methylation pattern was confirmed in 9 out of 10 HNSCCs. These findings are likely to be relevant in the epigenetic regulation of the DMR, especially in pathological conditions in which the imprinting of IGF2 and H19 genes is disrupted.

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“…A study examining the allelic expression of three imprinted genes (SNRPN, IMPT1, IGF2) in the normal population found evidence for significant biallelic expression indicating that functional variation at imprinted loci may be a common feature of the mammalian genome. 92 Association of DNA sequence variation with epigenetic variation -epi-alleles, epi-genotypes and epi-haplotypes As discussed above, few convincing associations between specific polymorphisms and susceptibility to MDD have been revealed by candidate gene studies. One major problem is the heterogeneity apparent in the data generated from these analyses.…”

Section: Parental Origin Effectsmentioning

confidence: 99%

Molecular studies of major depressive disorder: the epigenetic perspective

2007

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Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder encompassing a spectrum of symptoms involving deficits to a range of cognitive, psychomotor and emotional processes. As is the norm for aetiological studies into the majority of psychiatric phenotypes, particular focus has fallen on the interplay between genetic and environmental factors. There are, however, several epidemiological, clinical and molecular peculiarities associated with MDD that are hard to explain using traditional geneand environment-based approaches. Our goal in this study is to demonstrate the benefits of looking beyond conventional 'DNA þ environment' and 'DNA Â environment' aetiological paradigms. Epigenetic factors -inherited and acquired modifications of DNA and histones that regulate various genomic functions occurring without a change in nuclear DNA sequence -offer new insights about many of the non-Mendelian features of major depression, and provide a direct mechanistic route via which the environment can interact with the genome. The study of epigenetics, especially in complex diseases, is a relatively new field of research, and optimal laboratory techniques and analysis methods are still being developed. Incorporating epigenetic research into aetiological studies of MDD thus presents a number of methodological and interpretive challenges that need to be addressed. Despite these difficulties, the study of DNA methylation and histone modifications has the potential to transform our understanding about the molecular aetiology of complex diseases.

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Epigenetic Heterogeneity at Imprinted Loci in Normal Populations

Cited by 92 publications

References 32 publications

Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages

Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages

H19-DMR allele-specific methylation analysis reveals epigenetic heterogeneity of CTCF binding site 6 but not of site 5 in head-and-neck carcinomas: A pilot case-control analysis

Molecular studies of major depressive disorder: the epigenetic perspective

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