【点评】
    这一钻研在老鼠身上看到了后天营养情况通过表观遗传建饰影响了个别胎儿的基因表白，扭转了成年个别的代谢状态。

【参考论文】FASEB Journal, June 13, 2011 fj.11-181792; published ahead of print
Perinatal Undernutrition Affects the Methylation and Expression of the Leptin Gene in Adults: Implication for the Understanding of Metabolic Syndrome
C Jousse, L Parry, S Lambert-Langlais, et al.
Transient environmental influences, such as perinatal nutritional stress, may induce deleterious metabolic symptoms that last for the entire life of individuals, implying that epigenetic modifications play an important role in this process. We have investigated, in mice, the consequences of maternal undernutrition during gestation and lactation on DNA methylation and expression of the leptin gene, which plays a major regulatory role in coordinating nutritional state with many aspects of mammalian biology. We show that animals born to mothers fed a low-protein-diet (F1-LPD group) have a lower body weight/adiposity and exhibit a higher food intake than animals born to mothers fed a control diet (F1-CD group). These modifications persisted throughout life and were associated with lower levels of leptin mRNA and protein in starved F1-LPD mice, emphasizing that maternal protein-undernutrition affects the balance between food intake and energy expenditure in adults. Moreover, this nutritional stress resulted in the removal of methyls at CpGs located in the promoter of leptin, causing a permanent specific modification in the dynamics of the expression of leptin, which exhibits a stronger induction in the F1-LPD than in F1-CD mice in response to a meal. This study is an example of a molecular rationale linking transient environmental influences to permanent phenotypic consequences.

3. 新化合物通过阻断对高氧化压力的适应来选择性杀死癌细胞
【动态】
　　激活癌基因的突变和失活肿瘤抑造基因的突变所驱动的细胞恶变导致时时与升高的细胞压力（如氧化、复造、代谢和蛋白毒性压力、DNA危险）有关的细胞失调。为了生计，癌细胞必须适应这种压力，了局癌细胞可能变得依赖那些泛泛在正常细胞中不起如此关键作用的非癌基因。因而，在表型变换使仉对这类非癌基因依赖性可能造成报答的致命相互作用和选择性癌细胞殒命。利用基于细胞的幼分子筛选和定量的蛋白组学步骤客观地鉴别出可能选择性杀死癌细胞而非正常细胞的幼分子。不论p53是何情况，来自胡椒的天然产品荜茇酰胺在癌细胞和设计带有癌基因型的通常细胞中都能增长活性氧自由基水平和细胞凋亡，但它对快割裂或者慢割裂的根基正常细胞作用很幼。在异种移植肿瘤模型老鼠中观察到荜茇酰胺显著的抗肿瘤作用，而对正常老鼠无显著毒性。并且，荜茇酰胺强力抑造老鼠自觉形成的恶性乳腺肿瘤的成长和转移。该钻研了局批注一种幼分子能选择性地在有癌基因型的细胞中通过靶向在癌基因表白时产生的应对转变引起的氧化压力的非癌基因依赖性来诱导该细胞凋亡。

【点评】
　选择性阻断癌细胞对环境的适应从而让环境成分引起癌细胞凋亡。该钻研中的荜茇酰胺对处于高氧化压力下的癌细胞中的抗氧化酶在其浓度超出正常细胞中的水平时有抑造作用，从而选择性地诱导癌细胞在氧化压力下凋亡。这一点对钻研恒峰g22再生物质的抗癌作用机理有启迪。

【参考论文】Nature, 2011; 475 (7355): 231 DOI: 10.1038/nature10167
Selective killing of cancer cells by a small molecule targeting the stress response to ROS
Lakshmi Raj, Takao Ide, Aditi U. Gurkar, et al.
Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.

4. 诱导多能干细胞的表观遗传记忆
【动态】  
    人诱导多能干细胞看似极度像人胚胎干细胞。以色列科学家用两种遗传谱系追踪系统证了然从人胰岛β细胞天生诱导多能干细胞系。这些重组的细胞获得了多能干细胞的象征并分化成三胚层。然而，从β细胞而来的诱导多能干细胞(BiPSCs)在关键β细胞基因上维持盛开的染色质结构，同时有一个怪异的DNA甲基化署名以区别于其他多能干细胞。与胚胎干细胞和同基因的非β细胞来的iPSCs 相比，BiPSCs也显示了更高的体内体表分化成出产胰岛素的细胞的能力。其钻研了局提醒表观遗传记忆可能使BiPSCs更偏差于分化成出产胰岛素的细胞。这些发现证明人诱导多能干细胞的阐发型可能受其起源细胞的影响，也提醒其受影响的分化潜力可能有利于细胞代替医治。

【点评】
    该钻研的诱导多能干细胞可能偏差性地分化成其起源细胞，看似技术进取，实则无奈之举，由于人们无法驾驭诱导多能干细胞，不知路若何创造性命的前提使诱导多能干细胞可能正常分化成任何必要的细胞。此表，诱导多能干细胞基因组的扭转使其再也不是正常细胞，成为人造细胞。

【参考论文】Cell Stem Cell, 2011; 9 (1): 17 DOI:10.1016/j.stem.2011.06.007
Epigenetic Memory and Preferential Lineage-Specific Differentiation in Induced Pluripotent Stem Cells Derived from Human Pancreatic Islet Beta Cells
Ori Bar-Nur, Holger A. Russ, Shimon Efrat, Nissim Benvenisty.
Human induced pluripotent stem cells (HiPSCs) appear to be highly similar to human embryonic stem cells (HESCs). Using two genetic lineage-tracing systems, we demonstrate the generation of iPSC lines from human pancreatic islet beta cells. These reprogrammed cells acquired markers of pluripotent cells and differentiated into the three embryonic germ layers. However, the beta cell-derived iPSCs (BiPSCs) maintained open chromatin structure at key beta-cell genes, together with a unique DNA methylation signature that distinguishes them from other PSCs. BiPSCs also demonstrated an increased ability to differentiate into insulin-producing cells both in vitro and in vivo, compared with ESCs and isogenic non-beta iPSCs. Our results suggest that the epigenetic memory may predispose BiPSCs to differentiate more readily into insulin producing cells. These findings demonstrate that HiPSC phenotype may be influenced by their cells of origin, and suggest that their skewed differentiation potential may be advantageous for cell replacement therapy.

5. 幼RNA领导人纤维母细胞转造成神经元
【动态】
    神经元的转录因子和进化上守旧的信号通路被发现是有助于神经元的形成。然而，幼RNA在神经新生中的领导作用还不明显。美国科学家最近发现miR-9* 和miR-124领导SWI/SNF-like BAF 染色质重塑复合体组分的变动，该过程对神经元分化和职能很重要。在靠近神经元祖细胞有丝割裂出口时，miR-9* 和miR-124抑造神经元祖细胞BAF 染色质重塑复合体的BAF53a 亚基。在有丝割裂出口之后，BAF53a 被BAF53b取代，BAF45a被 BAF45b 和 BAF45c取代，后者归并成为神经元特异的BAF复合体为有丝割裂后的职能所必须。由于miR-9* 和miR-124也节造多个调节神经元分化和职能的基因，他们以为这些幼RNA可能与神经元命运有关。他们的钻研显示人纤维母细胞中miR-9/9* 和miR-124的表白诱导其转造成神经元，该过程受NEUROD2的推进。进一步参与神经元的转录因子ASCL1 和 MYT1L提高了转化率和转化成的神经元的成熟，这其中只表白这些转录因子不表白miR-9/9*-124 的话是没有成果的。该钻研暗示涉及miR-9/9*-124的遗传线路对神经元命运决定有领导作用。

【点评】
    幼RNA领导人纤维母细胞转造成神经元，揭示了表观调控对细胞分化的节造。表观调控的钻研将是比基因组钻研更有实用价值的课题。

【参考论文】Nature, 2011; DOI:10.1038/nature10323
MicroRNA-mediated conversion of human fibroblasts to neurons
Andrew S. Yoo, Alfred X. Sun, Li Li, et al.
Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.

6. 多能神经干细胞天生大脑中的神经元和胶质细胞
【动态】
    神经元天生和胶质天生在成体哺乳动物大脑的分立的区域持续进行。一个尚未解决的根基问题是细胞天生是来自谱系限度的祖细胞还是来自成体大脑中自我更新的多能神经干细胞。美国科学家的最新钻研选取遗传象征战术在成大哥鼠齿状回中追踪单个的、静止的、表白巢蛋白的放射状胶质样前体细胞（RGL）
？寺》治龇⑾侄嘀旨せ頡GL的方式，蕴含不合称和对称自我更新。体内的持久谱系追踪显示有显著比例的克隆蕴含RGLs、神经元和星形胶质细胞，批注单个RGL可能自我更新同时进行多谱系分化。此表，在RGL中有前提地去除Pten一路头推进其激活和对称的自我更新，但最终导致星形胶质细胞的终极分化和成体海马区RGL的耗竭。该钻研鉴定RGL为自我更新的多能神经干细胞，提供了体内成体神经干细胞个性的新见解。

【点评】
    体内的克隆分析揭示自我更新和成体多能神经干细胞个性，对于神经新生过程有了进一步相识。