許多類型的細胞能借由基因組重編程對環(huán)境產生差異性的應答,。那么固定的DNA藍本是如何靈活應對環(huán)境信號改變的呢,？表觀遺傳學修飾在不改變DNA序列的情況下控制著基因的表達,，包括染色質重塑,、組蛋白修飾,、DNA甲基化和microRNA通路,。營養(yǎng)等環(huán)境因素會影響細胞代謝,，而近日代謝與表觀遺傳學之間的關聯(lián)開始浮出水面。本期Science雜志上發(fā)表了兩項研究,，Shimazu和Shyh-Chang等人的這兩篇文章進一步加深了人們對上述關聯(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,，涉及轉錄的激活與沉默,、DNA修復和重組等。負責這類修飾的酶以代謝物作為乙?；蚣谆鶊F的來源,，這些代謝物的含量和定位決定了酶促反應的有效性和特異性。在乙?；?，細胞代謝物乙酰輔酶A（acetyl-CoA）和NAD+就是相應表觀遺傳學修飾酶的輔酶，能夠調控基因表達,。例如,，組蛋白乙酰轉移酶（HAT）的乙酰化依賴于局部乙酰輔酶A的亞細胞濃度,。
組蛋白去乙?；福℉DAC）負責去乙酰化,，其中III類HDAC在結構上與酵母的沉默信息調節(jié)因子2（Sir2）相似。哺乳動物HDAC中的sirtuin家族（酵母Sir2直系同源）有七個成員（SIRT1到SIRT7）,，這七個成員各有著獨特的亞細胞定位,。科學家們認為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，不過其詳細機制還有待進一步研究,。研究顯示,，禁食階段NAD+的細胞濃度高，提升了SIRT1的活力,。而當能量過量時,，NAD+很快轉化為NADH，使其濃度迅速降低,。由此營養(yǎng),、能量代謝和表觀遺傳學調控緊密聯(lián)系了起來。
SIRT曾被認為是依賴內源代謝物的唯一HDAC,，因為此前其他去乙酰酶從未與細胞代謝直接相關,。但事實也許并非如此。丁酸鹽是一種HDAC抑制劑,，會引發(fā)細胞周期停滯,、細胞凋亡和多種癌細胞變異，并導致乙?；M蛋白累積,。人們認為丁酸鹽的作用機制是阻斷了內源底物進入HDAC活性位點。Shimazu等人發(fā)現(xiàn),，結構上與丁酸鹽相似的酮體βOHB就是內源性的HDAC底物,。
酮體是在脂肪酸分解釋放能量時產生的。Shimazu等人在細胞實驗中發(fā)現(xiàn)βOHB是HDAC的內源抑制子,，會增加組蛋白H3的Lys9和Lys14乙?；せ钣赊D錄因子FOXO3a控制的一些基因轉錄,，而這種轉錄因子在多種生物中都與長壽有關,。這些研究結果支持了人們觀察到的一些現(xiàn)象：在熱量限制過程中哺乳動物體內βOHB濃度升高，并由此抵抗該條件下產生的氧化壓力,。在果蠅,、線蟲和酵母研究中，I類HDAC都涉及了熱量限制延長壽命的作用,，說明提高βOHB濃度的環(huán)境（如熱量限制）,，可通過抑制I類HDAC來延長壽命。
碳水化合物含量低的飲食會誘導酮體生成,，從而保護神經并增強神經元對氧化損傷的抵抗力,。Shimazu等人的研究顯示，這類飲食條件可能通過βOHB產生效果，增加抗氧化基因的表達,。顯然,，代謝物控制的組蛋白乙酰化是一個被廣泛采用的機制,。
組蛋白H3的Lys9和Lys14乙?；３ＥcLys4甲基化關聯(lián)，為轉錄激活創(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物控制機制呢？S-腺苷甲硫氨酸SAM是細胞中主要的甲基基團來源,。Shyh-Chang等人將這一問題與小鼠胚胎干細胞mESC的分化聯(lián)系起來,。雖然原因不明，不過小鼠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.
