世界生命科學(xué)前沿動態(tài)周報（四十六）

【點評】
線粒體是細(xì)胞生命活動的主導(dǎo)，線粒體本身的代謝活動因而對細(xì)胞至關(guān)重要。對于線粒體代謝活動的任何深入了解都會極大地幫助我們發(fā)現(xiàn)維持細(xì)胞正常生命活動的條件。

【參考論文】Cell Metabolism, 2011; 13 (5): 527-539 DOI: 10.1016/j.cmet.2011.04.002
MTERF4 Regulates Translation by Targeting the Methyltransferase NSUN4 to the Mammalian Mitochondrial Ribosome
Yolanda Cámara, Jorge Asin-Cayuela, Chan Bae Park, et al.
Precise control of mitochondrial DNA gene expression is critical for regulation of oxidative phosphorylation capacity in mammals. The MTERF protein family plays a key role in this process, and its members have been implicated in regulation of transcription initiation and site-specific transcription termination. We now demonstrate that a member of this family, MTERF4, directly controls mitochondrial ribosomal biogenesis and translation. MTERF4 forms a stoichiometric complex with the ribosomal RNA methyltransferase NSUN4 and is necessary for recruitment of this factor to the large ribosomal subunit. Loss of MTERF4 leads to defective ribosomal assembly and a drastic reduction in translation. Our results thus show that MTERF4 is an important regulator of translation in mammalian mitochondria.

3. 突變組織干細(xì)胞類似腫瘤干細(xì)胞
【動態(tài)】
　　上皮干細(xì)胞自我更新的同時維持多能性，已知缺少蛋白激酶MAP3K4的滋養(yǎng)層干細(xì)胞（TS細(xì)胞）同時維持了干細(xì)胞特性和上皮-間質(zhì)過渡態(tài)特性。美國北卡大學(xué)的新研究顯示MAP3K4控制了組蛋白乙酰基轉(zhuǎn)移酶CBP的活動，而維持上皮表型需要CBP來乙?；M蛋白H2A 和 H2B。 MAP3K4/CBP的活性同時缺失抑制了上皮基因的表達(dá)導(dǎo)致TS 細(xì)胞在維持其自我更新和多能性的同時進(jìn)行EMT上皮-間質(zhì)轉(zhuǎn)換。MAP3K4缺陷的TS 細(xì)胞的表達(dá)譜明確了一種 H2B 乙酰化調(diào)節(jié)的基因標(biāo)簽，與人體乳腺癌細(xì)胞的緊密重疊?？偟目磥?，該研究明確了一種表觀遺傳開關(guān)在TS細(xì)胞中維持其上皮表型并且揭示了前所未知的可能對乳腺癌起作用的基因。只改變了正常TS組織干細(xì)胞的一個氨基酸，這些突變干細(xì)胞在維持自我更新的同時表現(xiàn)出非常類似于預(yù)期是腫瘤干細(xì)胞特性的高轉(zhuǎn)移性和高侵襲性。

【點評】
　 腫瘤干細(xì)胞和正常組織干細(xì)胞共用某些分子信號機(jī)制，表觀調(diào)控決定著細(xì)胞命運(yùn)。正常組織干細(xì)胞能夠突變成腫瘤干細(xì)胞而針對腫瘤干細(xì)胞這些分子信號機(jī)制的干預(yù)也必然影響正常組織干細(xì)胞。

【參考論文Cell Stem Cell, Volume 8, Issue 5, 525-537, DOI:10.1016/j.stem.2011.03.008
MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells
Amy N. Abell, Nicole Vincent Jordan, Weichun Huang, et al.
Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4-deficient TS cells defines an H2B acetylation-regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveals previously unrecognized genes potentially contributing to breast cancer.

4. 乳腺癌細(xì)胞對雌激素信號的快速廣泛而短暫的轉(zhuǎn)錄反應(yīng)
【動態(tài)】  
美國西南醫(yī)學(xué)中心的新研究用GRO-seq方法測定了雌激素信號對乳腺癌細(xì)胞轉(zhuǎn)錄譜的直接作用。通過新的生物信息學(xué)方法分析所得數(shù)據(jù)使我們能夠直接從中鑒別出轉(zhuǎn)錄物。發(fā)現(xiàn)雌激素信號以快速、強(qiáng)力和出乎預(yù)料的短暫方式直接調(diào)節(jié)很大部分轉(zhuǎn)錄譜。除了編碼蛋白的基因，雌激素還調(diào)節(jié)所有三種RNA聚合酶的分布和作用以及幾乎每一種迄今發(fā)現(xiàn)的非編碼RNA。該研究結(jié)果最全面的測定了迄今主要的和直接的雌激素作用，提供資源幫助理解其他體系中快速信號依賴的轉(zhuǎn)錄活動。雌激素是乳腺癌生長的起始驅(qū)動力。

【點評】
雌激素對轉(zhuǎn)錄譜的快速廣泛的作用表明了非基因因素及表觀調(diào)控對生命活動的巨大影響。

【參考論文】 Cell, 05 May 2011 DOI: 10.1016/j.cell.2011.03.042
A Rapid, Extensive, and Transient Transcriptional Response to Estrogen Signaling in Breast Cancer Cells
Nasun Hah, Charles G. Danko, Leighton Core, et al.
We report the immediate effects of estrogen signaling on the transcriptome of breast cancer cells using global run-on and sequencing (GRO-seq). The data were analyzed using a new bioinformatic approach that allowed us to identify transcripts directly from the GRO-seq data. We found that estrogen signaling directly regulates a strikingly large fraction of the transcriptome in a rapid, robust, and unexpectedly transient manner. In addition to protein-coding genes, estrogen regulates the distribution and activity of all three RNA polymerases and virtually every class of noncoding RNA that has been described to date. We also identified a large number of previously undetected estrogen-regulated intergenic transcripts, many of which are found proximal to estrogen receptor binding sites. Collectively, our results provide the most comprehensive measurement of the primary and immediate estrogen effects to date and a resource for understanding rapid signal-dependent transcription in other systems.

5. 無抗原刺激激活沉寂的T細(xì)胞
【動態(tài)】
    第一次有直接證據(jù)表明蛋白Foxp1主動維持T細(xì)胞的沉寂狀態(tài)直到其被免疫系統(tǒng)的其它部分喚醒。敲除Foxp1蛋白的老鼠T細(xì)胞被激活行使其警戒功能。轉(zhuǎn)錄因子Foxp1執(zhí)行必需的天然T細(xì)胞沉寂狀態(tài)的細(xì)胞內(nèi)在調(diào)節(jié)。美國Wistar研究所報道了缺少轉(zhuǎn)錄因子Foxp1的成熟的天然CD8+T細(xì)胞獲得了效應(yīng)器表型和功能并且在體外直接響應(yīng)IL-7 而增殖。Foxp1拮抗Foxo1而抑制IL-7Rα的表達(dá)，負(fù)向調(diào)節(jié)激酶MEK和ErK的信號。在淋巴細(xì)胞充盈的老鼠中快速刪除Foxp1 誘導(dǎo)了天然T細(xì)胞獲得效應(yīng)器表型并增殖。Foxp1缺陷的天然CD8+T細(xì)胞甚至能夠在缺乏主要的I類組織相容性復(fù)合物的淋巴細(xì)胞減少性老鼠中增殖。該研究證明了淋巴細(xì)胞沉寂是通過包括轉(zhuǎn)錄調(diào)節(jié)在內(nèi)的主動維持機(jī)制獲得的。

【點評】
該研究證明免疫細(xì)胞的待命狀態(tài)并不是簡單的被動默認(rèn)功能，而是一個涉及到轉(zhuǎn)錄因子的主動控制過程。這一發(fā)現(xiàn)也說明了生命機(jī)制的精密和有秩序，但也為相關(guān)干預(yù)提供了可能。