許多類型的細(xì)胞能借由基因組重編程對(duì)環(huán)境產(chǎn)生差異性的應(yīng)答。那么固定的DNA藍(lán)本是如何靈活應(yīng)對(duì)環(huán)境信號(hào)改變的呢,？表觀遺傳學(xué)修飾在不改變DNA序列的情況下控制著基因的表達(dá),，包括染色質(zhì)重塑,、組蛋白修飾、DNA甲基化和microRNA通路,。營(yíng)養(yǎng)等環(huán)境因素會(huì)影響細(xì)胞代謝,，而近日代謝與表觀遺傳學(xué)之間的關(guān)聯(lián)開始浮出水面。本期Science雜志上發(fā)表了兩項(xiàng)研究,，Shimazu和Shyh-Chang等人的這兩篇文章進(jìn)一步加深了人們對(duì)上述關(guān)聯(lián)的了解,。
乙酰化和甲基化都是發(fā)生在特定殘基上的組蛋白翻譯后修飾，涉及轉(zhuǎn)錄的激活與沉默,、DNA修復(fù)和重組等,。負(fù)責(zé)這類修飾的酶以代謝物作為乙酰或甲基基團(tuán)的來(lái)源,，這些代謝物的含量和定位決定了酶促反應(yīng)的有效性和特異性。在乙?；?，細(xì)胞代謝物乙酰輔酶A（acetyl-CoA）和NAD+就是相應(yīng)表觀遺傳學(xué)修飾酶的輔酶，能夠調(diào)控基因表達(dá),。例如,，組蛋白乙酰轉(zhuǎn)移酶（HAT）的乙酰化依賴于局部乙酰輔酶A的亞細(xì)胞濃度,。
組蛋白去乙?；福℉DAC）負(fù)責(zé)去乙酰化,，其中III類HDAC在結(jié)構(gòu)上與酵母的沉默信息調(diào)節(jié)因子2（Sir2）相似,。哺乳動(dòng)物HDAC中的sirtuin家族（酵母Sir2直系同源）有七個(gè)成員（SIRT1到SIRT7），這七個(gè)成員各有著獨(dú)特的亞細(xì)胞定位,?？茖W(xué)家們認(rèn)為SIRT蛋白能夠感知熱量限制的有益生理作用，并涉及了線粒體能量代謝,、炎癥,、衰老和腫瘤形成，不過(guò)其詳細(xì)機(jī)制還有待進(jìn)一步研究,。研究顯示,，禁食階段NAD+的細(xì)胞濃度高，提升了SIRT1的活力,。而當(dāng)能量過(guò)量時(shí),，NAD+很快轉(zhuǎn)化為NADH，使其濃度迅速降低,。由此營(yíng)養(yǎng),、能量代謝和表觀遺傳學(xué)調(diào)控緊密聯(lián)系了起來(lái)。
SIRT曾被認(rèn)為是依賴內(nèi)源代謝物的唯一HDAC,，因?yàn)榇饲捌渌ヒ阴Ｃ笍奈磁c細(xì)胞代謝直接相關(guān),。但事實(shí)也許并非如此。丁酸鹽是一種HDAC抑制劑,，會(huì)引發(fā)細(xì)胞周期停滯,、細(xì)胞凋亡和多種癌細(xì)胞變異，并導(dǎo)致乙?；M蛋白累積,。人們認(rèn)為丁酸鹽的作用機(jī)制是阻斷了內(nèi)源底物進(jìn)入HDAC活性位點(diǎn),。Shimazu等人發(fā)現(xiàn)，結(jié)構(gòu)上與丁酸鹽相似的酮體βOHB就是內(nèi)源性的HDAC底物,。
酮體是在脂肪酸分解釋放能量時(shí)產(chǎn)生的,。Shimazu等人在細(xì)胞實(shí)驗(yàn)中發(fā)現(xiàn)βOHB是HDAC的內(nèi)源抑制子，會(huì)增加組蛋白H3的Lys9和Lys14乙?；?，激活由轉(zhuǎn)錄因子FOXO3a控制的一些基因轉(zhuǎn)錄，而這種轉(zhuǎn)錄因子在多種生物中都與長(zhǎng)壽有關(guān),。這些研究結(jié)果支持了人們觀察到的一些現(xiàn)象：在熱量限制過(guò)程中哺乳動(dòng)物體內(nèi)βOHB濃度升高,，并由此抵抗該條件下產(chǎn)生的氧化壓力。在果蠅,、線蟲和酵母研究中,，I類HDAC都涉及了熱量限制延長(zhǎng)壽命的作用，說(shuō)明提高βOHB濃度的環(huán)境（如熱量限制）,，可通過(guò)抑制I類HDAC來(lái)延長(zhǎng)壽命,。
碳水化合物含量低的飲食會(huì)誘導(dǎo)酮體生成，從而保護(hù)神經(jīng)并增強(qiáng)神經(jīng)元對(duì)氧化損傷的抵抗力,。Shimazu等人的研究顯示,，這類飲食條件可能通過(guò)βOHB產(chǎn)生效果，增加抗氧化基因的表達(dá),。顯然,，代謝物控制的組蛋白乙酰化是一個(gè)被廣泛采用的機(jī)制,。
組蛋白H3的Lys9和Lys14乙?；３ＥcLys4甲基化關(guān)聯(lián)，為轉(zhuǎn)錄激活創(chuàng)造了寬松的環(huán)境,。那么組蛋白甲基化是否也具有與乙?；愃频拇x物控制機(jī)制呢？S-腺苷甲硫氨酸SAM是細(xì)胞中主要的甲基基團(tuán)來(lái)源,。Shyh-Chang等人將這一問(wèn)題與小鼠胚胎干細(xì)胞mESC的分化聯(lián)系起來(lái),。雖然原因不明，不過(guò)小鼠mESC的多能性依賴蘇氨酸,。Shyh-Chang等人發(fā)現(xiàn),，SAM與S-腺苷同型半胱氨酸SAH之間的平衡關(guān)聯(lián)著H3的Lys4三甲基化，但同一殘基上的一甲基化和二甲基化則對(duì)這一平衡不那么敏感,。此外,，與其他位置的甲基化相比，H3的Lys4三甲基化對(duì)蘇氨酸代謝更為敏感。(生物谷Bioon.com)
DOI: 10.1126/science.1233423
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When Metabolism and Epigenetics Converge
Paolo Sassone-Corsi
Various cell types respond differently to the environment by using distinct circuits of genomic reprogramming. How does a fixed DNA blueprint allow flexibility in managing changes to environmental signals? Environmental inputs such as nutrition can modulate cell metabolism, and critical links between metabolism and epigenetic control—now widely thought to include chromatin remodeling, histone modifications, DNA methylation, and microRNA pathways (1)—are beginning to emerge (2, 3). Two reports in this issue, by Shimazu et al. (4) on page 211 and Shyh-Chang et al. (5) on page 222, provide insights into this connection.
DOI: 10.1126/science.1227166
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Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor
Tadahiro Shimazu1,2, Matthew D. Hirschey1,2, John Newman1,2, Wenjuan He1,2, Kotaro Shirakawa1,2,Natacha Le Moan3, Carrie A. Grueter4,5, Hyungwook Lim1,2, Laura R. Saunders1,2, Robert D. Stevens6,Christopher B. Newgard6, Robert V. Farese Jr.2,4,5, Rafael de Cabo7, Scott Ulrich8, Katerina Akassoglou3,Eric Verdin1,2,*
Concentrations of acetyl–coenzyme A and nicotinamide adenine dinucleotide (NAD+) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body D-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.
DOI: 10.1126/science.1226603
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Influence of Threonine Metabolism on S-Adenosylmethionine and Histone Methylation
Ng Shyh-Chang1,2,3,4,5,6, Jason W. Locasale5,6,*, Costas A. Lyssiotis5,6, Yuxiang Zheng5,6, Ren Yi Teo1,Sutheera Ratanasirintrawoot1,2,3, Jin Zhang1,2,3, Tamer Onder1,2,3, Juli J. Unternaehrer1,2,3, Hao Zhu1,2,3,John M. Asara5, George Q. Daley1,2,3,4,†, Lewis C. Cantley5,6,†
Threonine is the only amino acid critically required for the pluripotency of mouse embryonic stem cells (mESCs), but the detailed mechanism remains unclear. We found that threonine and S-adenosylmethionine (SAM) metabolism are coupled in pluripotent stem cells, resulting in regulation of histone methylation. Isotope labeling of mESCs revealed that threonine provides a substantial fraction of both the cellular glycine and the acetyl–coenzyme A (CoA) needed for SAM synthesis. Depletion of threonine from the culture medium or threonine dehydrogenase (Tdh) from mESCs decreased accumulation of SAM and decreased trimethylation of histone H3 lysine 4 (H3K4me3), leading to slowed growth and increased differentiation. Thus, abundance of SAM appears to influence H3K4me3, providing a possible mechanism by which modulation of a metabolic pathway might influence stem cell fate.
