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PNAS:父亲精子microRNA可能影响孩子脑发育

来源:生物谷 2015-10-21 11:28

                                 

(图片来自网络)
2015年10月21日讯 /生物谷BIOON/ --越来越多证据表明DNA并不是亲代将遗传信息传递到子代的唯一方式。亲代在一生当中经历的许多事件都会对遗传信息的传递产生影响。
 
最近,来自宾夕法尼亚大学的研究人员在国际学术期刊PNAS上发表了一项最新研究进展,他们在分子水平上发现了应激如何改变雄性小鼠的精子,并通过这种方式影响其后代对应激的应答情况。他们还发现这种变化是通过表观遗传学的方式或microRNA进行传递的,并非通过改变DNA。
 
在早期研究中,研究人员已经证实在交配之前通过更换笼盒或进行狐狸尿(捕猎者气味)暴露处理雄性小鼠,使其处于应激状态,其后代对应激的应答情况会存在障碍。研究人员将受到应激的雄性小鼠和未受到应激的雄性小鼠的精子进行对比分析,发现在应激小鼠精子中有9种microRNA表达出现升高。
 
为进一步证实这一结果,研究人员将这9种microRNA通过显微注射的方式注入小鼠受精卵,随后植入正常雌性小鼠体内进行繁殖,并以假注射或注射单个microRNA作为对照。当子代小鼠成年后,研究人员检测了这些小鼠对应激的应答情况。研究人员表示,检测结果与他们之前观察到的结果完全匹配。
 
当接受多microRNA注射的小鼠受到轻微应激,它们体内可的松水平更低,同时在室旁核中存在几百个基因出现显著的表达变化,这表明这些小鼠在早期神经发育过程中存在非常广泛的变化。
 
研究人员对这几个microRNA的靶向mRNA进行了分析,结果表明来自母亲卵细胞的mRNA受到了microRNA的攻击,并导致这些受到攻击的mRNA水平发生下降,研究人员还特别指出,这些受到影响的mRNA主要编码参与染色质重塑的蛋白分子。
 
研究人员表示,他们接下来准备对导致microRNA释放的上游因子进行进一步研究以及是否能够通过给予奖励等方式对上述过程进行干预,防止雄性亲代将异常应激反应传递给下一代。(生物谷Bioon.com)
 
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Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress
 
Ali B. Rodgers, Christopher P. Morgan, N. Adrian Leu, and Tracy L. Bale
 
Epigenetic signatures in germ cells, capable of both responding to the parental environment and shaping offspring neurodevelopment, are uniquely positioned to mediate transgenerational outcomes. However, molecular mechanisms by which these marks may communicate experience-dependent information across generations are currently unknown. In our model of chronic paternal stress, we previously identified nine microRNAs (miRs) that were increased in the sperm of stressed sires and associated with reduced hypothalamic-pituitary-adrenal (HPA) stress axis reactivity in offspring. In the current study, we rigorously examine the hypothesis that these sperm miRs function postfertilization to alter offspring stress responsivity and, using zygote microinjection of the nine specific miRs, demonstrated a remarkable recapitulation of the offspring stress dysregulation phenotype. Further, we associated long-term reprogramming of the hypothalamic transcriptome with HPA axis dysfunction, noting a marked decreased in the expression of extracellular matrix and collagen gene sets that may reflect an underlying change in blood-brain barrier permeability. We conclude by investigating the developmental impact of sperm miRs in early zygotes with single-cell amplification technology, identifying the targeted degradation of stored maternal mRNA transcripts including sirtuin 1 and ubiquitin protein ligase E3a, two genes with established function in chromatin remodeling, and this potent regulatory function of miRs postfertilization likely initiates a cascade of molecular events that eventually alters stress reactivity. Overall, these findings demonstrate a clear mechanistic role for sperm miRs in the transgenerational transmission of paternal lifetime experiences.
 
相关会议:2015第三届非编码RNA学术研讨会
 
 
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