世界生命科學(xué)前沿動態(tài)周報（五十）

【點評】
    該研究發(fā)現(xiàn)了除了雌激素與乳腺癌有關(guān)，雄性激素與乳腺癌也有關(guān)系。為治療雌激素受體陰性的乳腺癌患者的研究開辟了道路。

【參考論文】Cancer Cell, 2011; 20 (1): 119-131 DOI: 10.1016/j.ccr.2011.05.026
Targeting Androgen Receptor in Estrogen Receptor-Negative Breast Cancer
Min Ni, Yiwen Chen, Elgene Lim, et al.
Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25% 30% of cases that are ER negative (ER ). Androgen receptor (AR) is expressed in 60% 70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER /HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER /HER2+ breast cancers.

3. 定量的表觀遺傳記憶背后的基于多梳的開關(guān)
【動態(tài)】
　　保守的多梳抑制復(fù)合物2（PRC2）進(jìn)行的組蛋白3賴氨酸27三甲基化（H3K27me3）與穩(wěn)定的表觀遺傳靜默有關(guān)。對PRC2誘導(dǎo)的基因靜默已有很多了解，但關(guān)鍵問題還是關(guān)于它的聚集和穩(wěn)定性。植物對冬天的感知和記憶，即春化現(xiàn)象，在擬南芥是一個涉及基于PRC2的花抑制子FLC的靜默的經(jīng)典表觀遺傳過程。春化現(xiàn)象緩慢的動力學(xué)表現(xiàn)為在冷天需數(shù)周時間才能發(fā)生，在接下來的暖日子產(chǎn)生一定水平的定量取決于之前冷天長度的穩(wěn)定的FLC靜默。這些特點使春化現(xiàn)象成為理想的試驗體系來研究表觀遺傳狀態(tài)的維持和轉(zhuǎn)換。英國科學(xué)家使用數(shù)學(xué)模型、染色質(zhì)免疫沉淀和FLC:GUS報告分析，說明了在細(xì)胞數(shù)量取決于之前冷天數(shù)的一個細(xì)胞亞群中春化現(xiàn)象的數(shù)量化本性產(chǎn)生于H3K27me3介導(dǎo)的暖天FLC靜默。在冷天期間，在FLC上緊靠聚集區(qū)域的地方H3K27me3水平日漸增加。在冷天結(jié)束時，數(shù)字模擬預(yù)測這樣的一個聚集區(qū)域能夠轉(zhuǎn)換個別位置的雙穩(wěn)態(tài)的表觀遺傳狀態(tài)，通過靜默取決于冷天暴露時長的H3K27me3標(biāo)記而可能涵蓋整個FLC。因此，該模型預(yù)測了在單個細(xì)胞中FLC基因表達(dá)的一種雙穩(wěn)態(tài)模式，一種用FLC:GUS報告體系確認(rèn)的預(yù)測。該研究提出的轉(zhuǎn)換機(jī)制，涉及一個相反作用組蛋白修飾的局部聚集，很可能與廣泛的表觀遺傳重組有關(guān)。

【點評】
　該研究解釋了生物體如何對一些變化的環(huán)境條件形成生物學(xué)記憶，發(fā)現(xiàn)記憶機(jī)制是一類生物學(xué)開關(guān)并能遺傳給后代的表觀調(diào)控。

【參考論文】Nature, 2011; DOI:10.1038/nature10241
A Polycomb-based switch underlying quantitative epigenetic memory
Andrew Angel, Jie Song, Caroline Dean, Martin Howard.
The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between t em. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming.

4. 遺傳性乳腺癌遺傳預(yù)期與端?？s短相關(guān)
【動態(tài)】  
    越來越多的證據(jù)表明短的端粒和相應(yīng)的基因不穩(wěn)定性對細(xì)胞惡性轉(zhuǎn)變負(fù)有責(zé)任。家族性乳腺癌已觀察到有遺傳性。西班牙的科學(xué)家假設(shè)引發(fā)此病的基因缺陷會影響端粒的維護(hù)導(dǎo)致端?？s短，研究了家族性乳腺癌病人的端粒長度。他們首先研究了623個乳腺癌家族中母女對的發(fā)病年齡預(yù)期，分類為BRCA1, BRCA2, 和BRCAX。此外， 用定量PCR分析了198例遺傳性乳腺癌病人外周血白血球中DNA端粒的長度，并與267例對照樣本和71例偶發(fā)的乳腺癌病人樣本進(jìn)行了比較。同時也評估了乳腺癌家族母女對和對照樣本的端粒長度變化來查看代間差異，發(fā)現(xiàn)短的端粒是遺傳性而不是偶發(fā)性乳腺癌的特征。他們確定了一組帶有短端粒的乳腺癌家族BRCAX，提示端粒維護(hù)基因可能是乳腺癌的敏感基因。值得注意的是，他們描述了端粒的漸進(jìn)性縮短與受影響家族連續(xù)傳代時乳腺癌的越來越早發(fā)生有聯(lián)系，并為此提供了證據(jù)，提示這可能是遺傳性乳腺癌遺傳預(yù)期的機(jī)理。

【點評】
    該研究發(fā)現(xiàn)了端粒異常與遺傳性乳腺癌之間的關(guān)聯(lián)，即越來越短的端粒與越來越早發(fā)生遺傳性乳腺癌之間有關(guān)聯(lián)。

【參考論文】PLoS Genetics, 2011; 7 (7): e1002182 DOI:10.1371/journal.pgen.1002182
Genetic Anticipation Is Associated with Telomere Shortening in Hereditary Breast Cancer
Beatriz Martinez-Delgado, Kira Yanowsky, Lucia Inglada-Perez, et al.
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.

5. 人體誘導(dǎo)多能干細(xì)胞藏有致病性線粒體DNA突變
【動態(tài)】
    人體誘導(dǎo)多能干細(xì)胞最近被發(fā)現(xiàn)會藏有基因組修改，但重組細(xì)胞線粒體DNA的完整性還沒有研究。線粒體DNA突變率很高，被認(rèn)為對很多人體疾病負(fù)有責(zé)任。而且，線粒體DNA失去完整性可能會改變細(xì)胞的能量代謝，限制細(xì)胞分化。以前證明了誘導(dǎo)多能干細(xì)胞的產(chǎn)生與線粒體重構(gòu)和向糖解代謝轉(zhuǎn)換有關(guān)的一個德國研究組最近又測定了細(xì)胞重組對線粒體DNA的完整性的影響。針對線粒體DNA的大規(guī)模平行焦磷酸測序顯示來源于年輕健康供體的人體誘導(dǎo)多能干細(xì)胞藏有單個堿基的線粒體DNA突變（替換、插入、刪除），既有同質(zhì)的（在所有線粒體DNA分子）又有異質(zhì)的（在一部分線粒體DNA分子）。有趣的是，異質(zhì)性水平在來源于同一父代纖維母細(xì)胞的誘導(dǎo)多能干細(xì)胞系間也各不相同，這一現(xiàn)象很可能可用于開發(fā)生產(chǎn)來源于線粒體疾病患者的無線粒體DNA突變的誘導(dǎo)多能干細(xì)胞。通過整合轉(zhuǎn)錄、代謝和有效的生物能量學(xué)幾方面的數(shù)據(jù)，該研究揭示了帶有不同程度線粒體DNA突變的誘導(dǎo)多能干細(xì)胞系維持了恒定的人體胚胎干細(xì)胞樣的能量代謝重組。這包括過表達(dá)糖解酶，增加G6P的量，高表達(dá)PDK1蛋白，從而將生物能量流線路轉(zhuǎn)向糖解?？傊M管誘導(dǎo)多能干細(xì)胞中的線粒體DNA突變不影響重組相關(guān)的代謝調(diào)整，在分析誘導(dǎo)多能干細(xì)胞系時致病性線粒體DNA修飾的出現(xiàn)還是要監(jiān)控的一個重要方面。

【點評】
    誘導(dǎo)多能干細(xì)胞中的線粒體DNA突變雖不影響重組細(xì)胞的代謝路線調(diào)整，但依然存在比較高的致病風(fēng)險，大大限制了其實用性。