據(jù)美國物理學(xué)家組織網(wǎng)10月31日（北京時間）報道，最近,，美國埃默里大學(xué)醫(yī)學(xué)院和芝加哥大學(xué)研究人員合作,，繪制出了小鼠大腦中5-羥甲基胞嘧啶（5-hmC）的圖譜，顯示出該堿基從發(fā)育到老化的生命過程中隨基因組變化而變化的分布方式,。相關(guān)論文發(fā)表在《自然—神經(jīng)科學(xué)》雜志網(wǎng)站上。
此前的研究認(rèn)為,，5-羥甲基胞嘧啶只是一種過渡狀態(tài)的堿基,，而新圖譜表明，5-羥甲基胞嘧啶不止是一種中間狀態(tài),，其在干細(xì)胞和腦細(xì)胞中還有著特殊的平衡功能,，讓一種基因在被抑制之后重新打開。2009年,，科學(xué)家發(fā)現(xiàn)一種名為5-羥甲基胞嘧啶的新堿基大量分布于人體干細(xì)胞到腦細(xì)胞的DNA中,，并稱之為“第六種核苷酸”，擴(kuò)展了基因家族字母表,。
5-羥甲基胞嘧啶是一種表觀修飾胞嘧啶,。胞嘧啶是構(gòu)成DNA的4種堿基之一，表觀修飾是基因被打開或關(guān)閉發(fā)生的變化,，并非構(gòu)成DNA序列的部分,。5-羥甲基胞嘧啶和另外一種起修飾作用的DNA堿基5-甲基胞嘧啶(5-mC）很相似,，但它們之間的差異受到化學(xué)技術(shù)的限制一直無法分辨。
研究人員用一種化學(xué)標(biāo)記法給5-羥甲基胞嘧啶作了標(biāo)記,，研究了其在小鼠大腦發(fā)育過程中的分布變化,。結(jié)果發(fā)現(xiàn)，5-羥甲基胞嘧啶和5-甲基胞嘧啶不同,，5-羥甲基胞嘧啶更多出現(xiàn)在活躍基因中,，尤其是腦細(xì)胞，而5-甲基胞嘧啶通常出現(xiàn)在那些關(guān)閉基因或是基因組的重復(fù)“垃圾”區(qū),。當(dāng)干細(xì)胞變成了構(gòu)成血液,、肌肉和腦神經(jīng)的細(xì)胞時，5-甲基胞嘧啶會幫助關(guān)閉基因,，而且這些被關(guān)閉的基因不再打開,。
根據(jù)研究顯示，5-羥甲基胞嘧啶在DNA中只出現(xiàn)在5-甲基胞嘧啶曾經(jīng)出現(xiàn)過的地方,。這表明5-羥甲基胞嘧啶好像一種臨時信號,，預(yù)示著細(xì)胞將要清除5-甲基胞嘧啶標(biāo)記。
論文作者之一,、埃默里大學(xué)醫(yī)學(xué)院人類遺傳學(xué)副教授金鵬（音譯）表示,，目前他們正開始繪制雷特綜合征和自閉癥等神經(jīng)紊亂疾病中5-羥甲基胞嘧啶的變化方式，并打算進(jìn)一步提高探測分辨率,。（生物谷 Bioon.com）
doi:10.1038/nn.2959
PMC:
PMID:
5-hmC–mediated epigenetic dynamics during postnatal neurodevelopment and aging
Keith E Szulwach, Xuekun Li, Yujing Li, Chun-Xiao Song, Hao Wu, Qing Dai, Hasan Irier, Anup K Upadhyay, Marla Gearing, Allan I Levey, Aparna Vasanthakumar, Lucy A Godley, Qiang Chang, Xiaodong Cheng, Chuan He & Peng Jin
DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for ~40% of modified cytosine in the brain and has been implicated in DNA methylation–related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC–regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG–binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC–mediated epigenetic modification is critical in neurodevelopment and diseases.
