Tissue specific differentially methylated regions (TDMR): Changes in DNA methylation during development

Song, Fei; Mahmood, Saleh; Ghosh, Srimoyee; Liang, Ping; Smiraglia, Dominic J.; Nagase, Hiroki; Held, William A.

doi:10.1016/j.ygeno.2008.09.003

Cited by 120 publications

(105 citation statements)

References 44 publications

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“…The role of DNA methylation as a locking mechanism for an important event, such as tissue-specific gene expression during development, is well established (8,27,20). In particular, several studies of single muscle genes (2,12,18,37) have demonstrated a role of hypomethylation in the induction of muscle differentiation (21,29,31).…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Terruzzi¹,

Senesi

Montesano

et al. 2011

Physiological Genomics

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Terruzzi I, Senesi P, Montesano A, La Torre A, Alberti G, Benedini S, Caumo A, Fermo I, Luzi L. Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes. Physiol Genomics 43: 965-973, 2011. First published June 14, 2011 doi:10.1152/physiolgenomics.00040.2010.-Physical exercise induces adaptive changes leading to a muscle phenotype with enhanced performance. We first investigated whether genetic polymorphisms altering enzymes involved in DNA methylation, probably responsible of DNA methylation deficiency, are present in athletes' DNA. We determined the polymorphic variants C667T/A1298C of 5,10-methylenetetrahydrofolate reductase (MTHFR), A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR), G742A of betaine:homocysteine methyltransferase (BHMT), and 68-bp ins of cystathionine ␤-synthase (CBS) genes in 77 athletes and 54 control subjects. The frequency of MTHFR (AC), MTR (AG), and MTRR (AG) heterozygous genotypes was found statistically different in the athletes compared with the control group (P ϭ 0.0001, P ϭ 0.018, and P ϭ 0.0001), suggesting a reduced DNA methylating capacity. We therefore assessed whether DNA hypomethylation might increase the expression of myogenic proteins expressed during early (Myf-5 and MyoD), intermediate , and late-phase (MHC) of myogenesis in a cellular model of hypomethylated or unhypomethylated C2C12 myoblasts. Myogenic proteins are largely induced in hypomethylated cells [fold change (FC) ϭ Myf-5: 1.21, 1.35; MyoD: 0.9, 1.47; Myf-6: 1.39, 1.66; MHC: 1.35, 3.10 in GMA, DMA, respectively] compared with the control groups (FC ϭ Myf-5: 1.0, 1.38; MyoD: 1.0, 1.14; Myf-6: 1.0, 1.44; MHC: 1.0, 2.20 in GM, DM, respectively). Diameters and length of hypomethylated myotubes were greater then their respective controls. Our findings suggest that DNA hypomethylation due to lesser efficiency of polymorphic MTHFR, MS, and MSR enzymes induces the activation of factors determining proliferation and differentiation of myoblasts promoting muscle growth and increase of muscle mass. myogenesis; muscle hypertrophy; homocysteine cycle; muscle differentiation; hypertrophy PHYSICAL EXERCISE INDUCES considerable metabolic and morphological adaptive changes leading to an altered muscle phenotype with enhanced performance in trained individuals. The mechanism by which exercise exerts its action in athletes is still unclear. While environmental influences such as training scheme and diet are important, there is increasing evidence for strong genetic influences in athletic subjects. It is suggested that athletes possess some genetic advantage predisposing them to better sport performances than nonathletes. Thus, genotype may predict sport ability and performance (9, 41). Gene expression is controlled by an adequate supply of methyl groups to the DNA. Specific mechanisms (Fig. 1) take part in controlling DNA methylation (35): the methionine synthase enzyme (MS) uses MS-bound cobalamin cofactor as intermediate methyl-carrier and N5-methyltetrahy...

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Terruzzi¹,

Senesi

Montesano

et al. 2011

Physiological Genomics

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“…Possible reasons for this discrepancy include the differences inherent in measuring mRNA versus protein, differences in species (mouse and human), and differences in tissue-type (whole 9.5 dpc embryo and neuroblastoma samples). Furthermore, this particular locus has previously been identified to be differentially methylated in different tissues (Song et al, 2009), raising the possibility that the relationship between Zscan10 methylation and expression may in fact be tissue-specific.…”

Section: Discussionmentioning

confidence: 99%

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

Yamada¹

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The in utero environment is a critical determinant of the immediate and future health of the developing fetus. In Australia, two of the most commonly used drugs during pregnancy are alcohol and nicotine. Prolonged periods of gestational exposure to alcohol and nicotine, separately, have been associated with a range of adverse outcomes in the offspring, in both humans and experimental animal models. The consequences of ethanol and nicotine exposure restricted to early gestation on resultant offspring are poorly characterised, and few animal models exist to build greater understanding. Moreover, the immediate molecular changes associated with exposures to ethanol and/or nicotine restricted to early gestation has yet to be described.This thesis utilised mouse models of early gestational ethanol and/or nicotine exposure to explore the impact of each of these exposures on offspring growth, as well as their associated transcriptional and epigenetic changes. In each model, pregnant C57BL/6 dams were provided with ad libitum access to solutions of 10% ethanol and/or 100 µg/ml nicotine from fertilisation (0.5 dpc) to midgestation (8.5 dpc). The exposure window utilised in each of the models is developmentally equivalent to the first three to four weeks of a human pregnancy.Previously, our laboratory identified reduced growth, microcephaly, and gene expression changes in the liver and hippocampus of the postnatal offspring of the model of prenatal ethanol exposure utilised in this thesis. In contrast, at mid-gestation (9.5 dpc), there was no evidence of developmental delay (somite number), reduced growth (crown-rump length), or microcephaly.Further, a genome-wide gene expression microarray (targeting 30 855 genes) and a screen of the expression of 641 microRNAs, identified only one gene (Bcl11b) as differentially expressed in male 9.5 dpc whole embryos following the ethanol exposure. These data suggest that there is a delay between the ethanol exposure and the onset of adverse phenotypes -arguing that the embryo is somehow able to form a memory of the ethanol exposure. The absence of widespread transcriptional changes suggests that changes in embryonic mRNA and microRNA expression are unlikely to be major contributors to the memory of the exposure.A early gestational model of nicotine exposure was newly established in this thesis. This nicotine exposure resulted in an average serum cotinine (metabolite of nicotine) concentration similar to that reported in humans who smoke 10 to 15 cigarettes per day. This exposure was sufficient to induce a reduction in body size both at mid-gestation and postnatally, but not at late gestation. Furthermore, the increased expression of Zscan10 in the whole male 9.5 dpc embryo was identified and validated across multiple cohorts. Zscan10 encodes for a transcription factor expressed throughout development, with a proposed role in the regulation of progenitor cells. The increased expression of Zscan10 in the nicotine-exposed embryos was associated with a reduction in DNA methylation ...

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“…C57 BL/6J mice were purchased from Jackson Laboratory and maintained at Charles River Laboratories, Inc. (Yokohama, Japan). Brain specimens of the mice at three differential stages (15-day-old embryo; E15, new born; NB, 12-week adult; AD), were collected and stored as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

“…The CpG sites at CpG island (CpGi) of the Zfp206-exon 5 (human: ZNF206-exon 5) are reported as a testicular and neuronal-specific DMRs and they are demethylated during late stage of mouse brain and testis development (5,11). Here, we found that methylation state of the region associated with the ZNF206 expression and the homologous CpGi was aberrantly hypomethylated in human neuroblastomas, especially those with poor prognostic patients.…”

Section: Introductionmentioning

confidence: 91%

DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal differentiation in mice and development of neuroblastoma in humans

Kawashima

Sugito²,

Yoshizawa³

et al. 2011

Int J Oncol

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Abstract. Differentiation of human neuroblastoma recapitulates neural crest development. In our whole genome DNA methylation screening of tissue-specific differentially methylated regions (T-DMRs) and developmental stage specific differentially methylated regions (DS-DMRs) we reported that the exon 5 CpG island (CpGi) of Zfp206 (human: ZNF206), which was required to maintain embryonic stem cells in a pluripotent state, was one of potent brain and testis-specific T-DMRs in mice. In this study methylation level of the CpG sites at Zfp206-exon 5 CpGi in mouse brain samples at three different developmental stages (15-day-old embryo; E15, new born; NB, 12-week adult; AD) were quantitatively analyzed and it was identified that Zfp206-exon 5 CpGi was the DS-DMRs in mouse brain. In AD brains, Zfp206-exon 5 CpGi was significantly hypomethylated and Zfp206 expression was repressed, compared with E15 and NB brains. Hence, mehtylation level of human 5'-end of CpGi at ZNF206-exon 5, which is homologous CpGi to mice, was analyzed in neuroblastomas. Although all four adrenal samples showed complete methylation at the homologous region, we found the hypomethylation in 7 out of 26 neuroblastomas and a significant association between the hypomethylation and poor prognosis. In neuroblastoma cell lines and specimens, the hypomethylation was also associated with ZNF206 expression. These data indicated that the changes in DNA methylation levels at the Zfp206-exon 5 might be one of the important factors during neuronal development in mice and that the hypomethylation of the homologous region induced ZNF206 expression in humans and was associated with human neuroblastomagenesis. Even though the function of ZNF206 and its expression regulation in neuroblastoma remain elusive, ZNF206 might be a candidate differentiation suppressor and prognosis marker in neuroblastoma. IntroductionEpigenetic programing predetermines the developmental program and provides necessary direction for the multitude of changes that are required to proceed from a fertilized oocyte to a fully developed adult animal (1). It has been suggested that epigenetic changes are associated with development and differentiation. DNA methylation is one of the epigenetic factors and plays an important role in the diverse genomic process, such as gene regulation, chromosomal stability, parental imprinting and X-inactivation (2). Recent genome-wide DNA methylation searches indicate that 4-17% of CpG sites are different in methylation among tissues and developmental processes (3,4). Tissue-specific differentially methylated regions (T-DMRs) and developmental-specific differentially methylated regions (DS-DMRs) are suggested to play important roles in development and differentiation (5). Therefore, disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation (6). For example, Hox genes are involved in determining anterior-posterior embryonic pattern and govern DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal ...

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Tissue specific differentially methylated regions (TDMR): Changes in DNA methylation during development

Cited by 120 publications

References 44 publications

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

Genetic polymorphisms of the enzymes involved in DNA methylation and synthesis in elite athletes

A study of the consequences of early gestational ethanol and/or nicotine exposure in the mouse

DNA hypomethylation at the ZNF206-exon 5 CpG island associated with neuronal differentiation in mice and development of neuroblastoma in humans

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