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Science:当代谢遇上表观遗传学

  1. 代谢
  2. 表观遗传学

来源:Science 2013-03-14 10:03

许多类型的细胞能借由基因组重编程对环境产生差异性的应答。那么固定的DNA蓝本是如何灵活应对环境信号改变的呢?表观遗传学修饰在不改变DNA序列的情况下控制着基因的表达,包括染色质重塑、组蛋白修饰、DNA甲基化和microRNA通路。营养等环境因素会影响细胞代谢,而近日代谢与表观遗传学之间的关联开始浮出水面。

许多类型的细胞能借由基因组重编程对环境产生差异性的应答。那么固定的DNA蓝本是如何灵活应对环境信号改变的呢?表观遗传学修饰在不改变DNA序列的情况下控制着基因的表达,包括染色质重塑、组蛋白修饰、DNA甲基化和microRNA通路。营养等环境因素会影响细胞代谢,而近日代谢与表观遗传学之间的关联开始浮出水面。本期Science杂志上发表了两项研究,Shimazu和Shyh-Chang等人的这两篇文章进一步加深了人们对上述关联的了解。

乙酰化和甲基化都是发生在特定残基上的组蛋白翻译后修饰,涉及转录的激活与沉默、DNA修复和重组等。负责这类修饰的酶以代谢物作为乙酰或甲基基团的来源,这些代谢物的含量和定位决定了酶促反应的有效性和特异性。在乙酰化中,细胞代谢物乙酰辅酶A(acetyl-CoA)和NAD+就是相应表观遗传学修饰酶的辅酶,能够调控基因表达。例如,组蛋白乙酰转移酶(HAT)的乙酰化依赖于局部乙酰辅酶A的亚细胞浓度。

组蛋白去乙酰化酶(HDAC)负责去乙酰化,其中III类HDAC在结构上与酵母的沉默信息调节因子2(Sir2)相似。哺乳动物HDAC中的sirtuin家族(酵母Sir2直系同源)有七个成员(SIRT1到SIRT7),这七个成员各有着独特的亚细胞定位。科学家们认为SIRT蛋白能够感知热量限制的有益生理作用,并涉及了线粒体能量代谢、炎症、衰老和肿瘤形成,不过其详细机制还有待进一步研究。研究显示,禁食阶段NAD+的细胞浓度高,提升了SIRT1的活力。而当能量过量时,NAD+很快转化为NADH,使其浓度迅速降低。由此营养、能量代谢和表观遗传学调控紧密联系了起来。

SIRT曾被认为是依赖内源代谢物的唯一HDAC,因为此前其他去乙酰酶从未与细胞代谢直接相关。但事实也许并非如此。丁酸盐是一种HDAC抑制剂,会引发细胞周期停滞、细胞凋亡和多种癌细胞变异,并导致乙酰化组蛋白累积。人们认为丁酸盐的作用机制是阻断了内源底物进入HDAC活性位点。Shimazu等人发现,结构上与丁酸盐相似的酮体βOHB就是内源性的HDAC底物。

酮体是在脂肪酸分解释放能量时产生的。Shimazu等人在细胞实验中发现βOHB是HDAC的内源抑制子,会增加组蛋白H3的Lys9和Lys14乙酰化,激活由转录因子FOXO3a控制的一些基因转录,而这种转录因子在多种生物中都与长寿有关。这些研究结果支持了人们观察到的一些现象:在热量限制过程中哺乳动物体内βOHB浓度升高,并由此抵抗该条件下产生的氧化压力。在果蝇、线虫和酵母研究中,I类HDAC都涉及了热量限制延长寿命的作用,说明提高βOHB浓度的环境(如热量限制),可通过抑制I类HDAC来延长寿命。

碳水化合物含量低的饮食会诱导酮体生成,从而保护神经并增强神经元对氧化损伤的抵抗力。Shimazu等人的研究显示,这类饮食条件可能通过βOHB产生效果,增加抗氧化基因的表达。显然,代谢物控制的组蛋白乙酰化是一个被广泛采用的机制。

组蛋白H3的Lys9和Lys14乙酰化常常与Lys4甲基化关联,为转录激活创造了宽松的环境。那么组蛋白甲基化是否也具有与乙酰化类似的代谢物控制机制呢?S-腺苷甲硫氨酸SAM是细胞中主要的甲基基团来源。Shyh-Chang等人将这一问题与小鼠胚胎干细胞mESC的分化联系起来。虽然原因不明,不过小鼠mESC的多能性依赖苏氨酸。Shyh-Chang等人发现,SAM与S-腺苷同型半胱氨酸SAH之间的平衡关联着H3的Lys4三甲基化,但同一残基上的一甲基化和二甲基化则对这一平衡不那么敏感。此外,与其他位置的甲基化相比,H3的Lys4三甲基化对苏氨酸代谢更为敏感。(生物谷Bioon.com)

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.

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.

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.

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