Epigeneticsについて http://www.telegraph.co.uk/science/10369861/Epigenetics-How-to-alter-your-genes.html.

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Presentation on theme: "Epigeneticsについて http://www.telegraph.co.uk/science/10369861/Epigenetics-How-to-alter-your-genes.html."— Presentation transcript:

1 Epigeneticsについて

2 The Dutch Famine Birth Cohort Studies relate to babies born around a 5-month period of extreme food shortage during the winter of Numerous characteristics of mothers and offspring were obtained around birth and the offspring have been followed since. In one study, exposure to famine during gestation led to a higher cumulative incidence of coronary artery disease, as well as an earlier age at onset, than was found for those not exposed to famine during gestation. Moreover, these effects were found only if exposure to famine occurred early in gestation. Such correlative studies leave us to wonder: what could have happened during those first few months of development that became evident only years later? Painter, R.C., de Rooij, S.R., Bossuyt, P.M., et al. Am. J. Clin. Nutr. 84, (2006). 妊娠初期の(超)低栄養は子供の成人後の(不)健康に大きな影響を与える

3 君(男性)の今の食生活が 孫の健康に影響を与える!(かもしれない)
                                       以下12枚は主にこちらより You are what you eat! 君(男性)の今の食生活が 孫の健康に影響を与える!(かもしれない) Epigenetic inheritance adds another dimension to the modern picture of evolution. The genome changes slowly, through the processes of random mutation and natural selection. It takes many generations for a genetic trait to become common in a population. The epigenome, on the other hand, can change rapidly in response to signals from the environment. And epigenetic changes can happen in many individuals at once. Through epigenetic inheritance, some of the experiences of the parents may pass to future generations. At the same time, the epigenome remains flexible as environmental conditions continue to change. Epigenetic inheritance may allow an organism to continually adjust its gene expression to fit its environment - without changing its DNA code.

4 父/父方祖父の思春期前の栄養状態が悪いと心血管障害/糖尿病が少ない(Sweden Överkalix parish)
父方祖父の思春期前の栄養状態が悪いと孫の寿命が長い。32年以上! ある程度粗食がいいんですね!

5 Case in Point: Epigenetics in Hypertension高血圧 ホルモン調節も最終的にはEpigeneticな変化
Aldosterone is a corticosteroid hormone that, through mineralocorticoid receptors, alters the uptake and secretion of salts by collecting ducts of the kidneys, thus altering water uptake, blood volume, and blood pressure. Excess aldosterone contributes to arterial hypertension, congestive heart failure, chronic kidney disease, coronary artery disease, and stroke.4 Clearly, the mechanism of action of aldosterone at the kidney collecting duct must be important. One enzyme serves to hypermethylate the lysine residue 79 on histone 3 (H3K79). In yeast, ablation of this methyltransferase causes disruption of telomere silencing, leading to the name DOT1. A mouse DOT1 homolog, DOT1L, also hypermethylates H3K79 in mice, but this serves to repress the expression of a subset of genes. DOT1L binds to AF9, a DNA-binding protein which positions DOT1L only on those nucleosomes whose associated DNA has a sequence that is recognized by AF9. This confers selectivity for which nucleosomes are targeted for hypermethylation of H3K79 and which genes are consequently repressed. One such gene encodes a sodium channel subunit, epithelial Na+ channel subunit α (ENaCα). Aldosterone alters the expression of ENaCα by modulating the DOT1L/AF9 repressive complex (Figure 2). Aldosterone induces the expression of serum- and glucocorticoid-induced kinase 1 (Sgk1), which phosphorylates AF9 and disrupts the complex.5 Aldosterone also inhibits the expression of both DOT1L and AF9.6,7 These steps are necessary and sufficient to increase ENaCα expression in the presence of the hormone-receptor complex. It is worth noting that this pathway involves a short term and reversible mechanism involving histone modification. Such transient changes are the hallmark of the ‘signaling model’ of epigenetic modifications. These contrast with other pathways where histone modifications are inherited through cell division, the so-called ‘histone code hypothesis’ of epigenetic signaling.

6 Figure 2. Aldosterone promotes the phosphorylation of Af9 by Sgk1, dissociating DOT1L from Af9, allowing demethylation of H3K79 and the expression of ENaCα 4. Calhoun, D.A. Circulation 114, (2006). 5. Zhang, W., Xia, X., Reisenauer, M.R., et al. J. Clin. Invest. 117(3), (2007). 6. Zhang, W., Xia, X., Reisenauer, M.R., et al. J. Biol. Chem. 281(26), (2006). 7. Zhang, D., Yu, Z.-Y., Cruz, P., et al. Kidney Int. 75(3), (2009).

7 While obviously the diet of a pregnant mother can affect fetal developement, these studies indicate that dietary supplements, taken by the mother, may mark the genome of the fetus and affect adult health. In the viable yellow agouti (Avy) mouse, expression of the agouti gene leads to a switch from brown to yellow coat color (Figure 3). Moreover, adult agouti mice suffer from obesity, hyperlipidemia, and hypertension. The expression of the agouti gene is initiated from a cryptic promoter in a retrotransposon inserted in agouti pseudoexon 1A (PS1A). It’s known that cytosine methylation on the transposable element prevents agouti gene expression, producing a brown-coated mouse that is referred to as ‘pseudoagouti’. Waterland and Jirtle demonstrated that supplementing normal chow given to pregnant mice with methyl donors (folic acid, betaine, vitamin B12, choline) produced an increase in methylation of CpG sites within PS1A in the offspring and shifted the coat color distribution toward the brown (pseudoagouti) phenotype. These methylation patterns were found in cells from diverse tissues, showing that Avy methylation is determined in the early embryo and maintained with high fidelity throughout development. Waterland, R.A. and Jirtle, R.L. Mol. Cell. Biol. 23(15), (2003). Figure 3. Genetically identical week 15 littermates representing coat colors ranging from agouti (left) to pseudoagouti (right); Note differences in size

8 食餌の影響でIAP promoterがメチル化されると遺伝子を持っていても形質は発現しない
Comprehensive Toxicology 12: 69–88 Developmental Toxicology 2010 Figure 3. (a) The murine Avy metastable epiallele in which a cryptic promoter in the IAP promotes constitutive Agouti expression. (b) The degree of CpG methylation in the Avy IAP correlates with ectopic Agouti expression. Reprinted from Jirtle, R. L.; Skinner, M. K. Nat. Rev. Genet.2007, 8, 253–262, with permission from Nature Publishing Group (left) and Dr. Randy Jirtle and Environmental Health Perspective (right).

9 In another study, genistein, an isoflavonoid naturally found in soy, increased both PS1A methylation and frequency of pseudoagouti expression in offspring when added to the mother’s diet. Importantly, ectopic agouti expression is associated with adult-onset obesity, diabetes, and cancer. Hypermethylation of PS1A, in mice from genistein-fed mothers, persisted into adulthood, decreasing agouti expression, and, remarkably, protecting mice from obesity. Conversely, hypomethylation of PS1A, following exposure to the common chemical bisphenol A (BPA), increased agouti expression; BPA is known to promote obesity, hyperlipidemia, and hypertension in mice. Taken together, these results demonstrate that maternal diet has in utero effects on the epigenome of the early embryo that can alter susceptibility to disease into adulthood. 環境ホルモン、食肉の抗生物質なども影響する!

10 その他の同様の研究 Gestational diabetes Mammals can experience a hormone-triggered type of diabetes during pregnancy, known as gestational diabetes. When the mother has gestational diabetes, the developing fetus is exposed to high levels of the sugar glucose. High glucose levels trigger epigenetic changes in the daughter's DNA, increasing the likelihood that she will develop gestational diabetes herself. Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero. Diabetes : 母親の妊娠期糖尿病は子供のtype II糖尿病・妊娠糖尿病の誘因となる

11 Nurturing behavior in rats Rat pups who receive high or low nurturing from their mothers develop epigenetic differences that affect their response to stress later in life. When the female pups become mothers themselves, the ones that received high quality care become high nurturing mothers. And the ones that received low quality care become low nurturing mothers. The nurturing behavior itself transmits epigenetic information onto the pups' DNA, without passing through egg or sperm. 手厚い育児環境で育った子供は良い母になる

12 Epigenetic modifications in reproduction and development
全体として一旦リセットされるのだが、親の環境影響による影響の一部は残る。 その後生殖細胞の分化に伴い変化。父母で状態の異なるImprinting遺伝子あり。 初期段階で広範にリセット その後細胞分化に伴い変化

13 お腹の中には孫の世代がいる!

14 Maternal diet and aging alter the epigenetic control of a promoter–enhancer interaction at the Hnf4a gene in rat pancreatic islets PNAS 108 (13)  , 2011 肝細胞核因子4α Environmental factors interact with the genome throughout life to determine gene expression and, consequently, tissue function and disease risk. One such factor that is known to play an important role in determining long-term metabolic health is diet during critical periods of development. Epigenetic regulation of gene expression has been implicated in mediating these programming effects of early diet. The precise epigenetic mechanisms that underlie these effects remain largely unknown. Here, we show that the transcription factor Hnf4a, which has been implicated in the etiology of type 2 diabetes (T2D), is epigenetically regulated by maternal diet and aging in rat islets. Transcriptional activity of Hnf4a in islets is restricted to the distal P2 promoter through its open chromatin configuration and an islet-specific interaction between the P2 promoter and a downstream enhancer. Exposure to suboptimal nutrition during early development leads to epigenetic silencing at the enhancer region, which weakens the P2 promoter–enhancer interaction and results in a permanent reduction in Hnf4a expression. Aging leads to progressive epigenetic silencing of the entire Hnf4a locus in islets, an effect that is more pronounced in rats exposed to a poor maternal diet. Our findings provide evidence for environmentally induced epigenetic changes at the Hnf4a enhancer that alter its interaction with the P2 promoter, and consequently determine T2D risk. We therefore propose that environmentally induced changes in promoter-enhancer interactions represent a fundamental epigenetic mechanism by which nutrition and aging can influence long-term health.

15 子の脂肪細胞WATでの遺伝子発現・DNAメチル化:妊娠期に過食→子供に脂肪がつきやすい
これを引用する論文 Maternal obesity enhances white adipose tissue differentiation and alters genome- scale DNA methylation in male rat offspring. Endocrinology (11) 子の脂肪細胞WATでの遺伝子発現・DNAメチル化:妊娠期に過食→子供に脂肪がつきやすい Maternal obesity has little effect on the immediate offspring but impacts on the next generation. Endocrinology (7)  次の世代の胎児に影響 Maternal taurine supplementation in rats partially prevents the adverse effects of early-life protein deprivation on b-cell function and insulin sensitivity. Reproduction (6) 妊娠期に低栄養だと生まれた子供は糖尿病になりやすい(Catch-up growth)Taurine添加で改善 Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes (12)  家族に糖尿病歴のある人について筋肉のDNAメチル化を調べた:6ヶ月の 運動療法で改善 Reducing maternal weight improves offspring metabolism and alters (or modulates) methylation. PNAS 110: 12859–12860, 2013 gastrointestinal bypass surgery(胃腸バイパス手術)前後での比較

16 臍帯血DNAメチル化解析・遺伝子発現データと母親の栄養状態・子供の肥満状態の対応
preterm and on term babiesそれぞれで Fast growerとslow growerの比較 子供のDNAメチル化状態に対する必要因子(葉酸・V.B12)・メチル基供給酵素遺伝子の影響 氏/育ち(Nature/Nurture)同程度の影響

17 Chromatin structure for understanding Epigenetics: excerpt from Essentials細胞生物学 翻訳原著第三版 南江堂 要は、DNA染色体のほどけたところ(Euchromatin)とコンパクトに収納された所(Heterochromatin)を作り、それを細胞分裂・世代を経ても維持する

18 J Cell Sci 114: 2711,2001

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20 Writers, Readers and Erasers
Histone modification (Me-/Ace-) +DNA cytosine methylation

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23 Epigeneticな変化の拡散を抑えるInsulator領域もある:これにタンパク質因子が結合して活性化,メチル化されれば不活性に

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26 動原体Kinetochore on the Centromere
Fig 単純なセントロメア構造のモデル。酵母Saccharomyces cerevisiaeでは,特定のセントロメアDNA塩基配列が,通常のH3に代わって変異H3ヒストン(たいていの生物でCENP-Aとよばれる)を2分子もつヌクレオソームを構築する。この変種ヒストンに固有なアミノ酸配列は。さらにタンパク質を集合させ,そのうちいくつかが動原体を形成する。この動原体は,微小管を1本だけ捕捉する点でほかと異なる。(ヒトでは20本以上)

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