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PLoS Genetics:浙江大学何向伟研究组阐述DNA复制应激对核小体复制表观遗传稳定性的影响及其分子

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摘要 : 2017年7月27日,国际顶级学术期刊《PLOS genetics》发表了浙江大学生命科学研究院何向伟教授实验室题为“Replication stress affects the fidelity of nucleosome-mediated epigenetic inheritance”的研究论文。

2017年7月27日,国际顶级学术期刊《PLOS genetics》发表了浙江大学生命科学研究院何向伟教授实验室题为“Replication stress affects the fidelity of nucleosome-mediated epigenetic inheritance”的研究论文。专职科研人员李文珠是本文第一作者,何向伟教授是本文通讯作者。

表观遗传通过对基因表达的调控,在许多基本生物现象如发育和人类疾病中,起着关键作用。作为一种信息传递机制,它的最基本考量参数之一就是稳定性,即表观特征代代相传的精确程度。然而,与DNA介导的遗传机制的研究相比,由于缺乏合适的实验手段对表观遗传稳定性进行定量分析,对表观遗传稳定性及其调控分子机制的系统性研究基本还是空白。

何向伟教授实验室在单细胞模式生物裂殖酵母中,首创了表观遗传稳定性的定量测定方法。利用这个方法,他们发现DNA复制应激会导致核小体复制的表观遗传稳定性的降低。他们的工作支持了下述分子机制模型,即:DNA复制应激时会过度生成单链DNA,同时导致大量亲本组蛋白在复制叉附近累积,直接导致亲本组蛋白在核小体重组装时错误地定位,从而降低核小体复制的表观遗传稳定性。这些发现揭示了DNA复制应激对表观遗传的干扰作用,并且为进一步阐明表观遗传稳定性的调控机制及其在肿瘤发生和干细胞诱导等重大生物医学问题中的应用提示了研究方向。

PLoS Genetics:浙江大学何向伟研究组阐述DNA复制应激对核小体复制表观遗传稳定性的影响及其分子
原文链接:

Replication stress affects the fidelity of nucleosome-mediated epiGENEtic inheritance

原文摘要:

The fidelity of epigenetic inheritance or, the precision by which epigenetic information is passed along, is an essential parameter for measuring the effectiveness of the process. How the precision of the process is achieved or modulated, however, remains largely elusive. We have performed quantitative measurement of epigenetic fidelity, using position effect variegation (PEV) in Schizosaccharomyces pombe as readout, to explore whether replication perturbation affects nucleosome-mediated epigenetic inheritance. We show that replication stresses, due to either hydroxyurea treatment or various forms of genetic lesions of the replication machinery, reduce the inheritance accuracy of CENP-A/Cnp1 nucleosome positioning within centromere. Mechanistically, we demonstrate that excessive formation of single-stranded DNA, a common molecular abnormality under these conditions, might have correlation with the reduction in fidelity of centromeric chromatin duplication. Furthermore, we show that replication stress broadly changes chromatin structure at various loci in the genome, such as telomere heterochromatin expanding and mating type locus heterochromatin spreading out of the boundaries. Interestingly, the levels of inheritable expanding at sub-telomeric heterochromatin regions are highly variable among independent cell populations. Finally, we show that HU treatment of the multi-cellular organisms C. elegans and D. melanogaster affects epigenetically programmed development and PEV, illustrating the evolutionary conservation of the phenomenon. Replication stress, in addition to its demonstrated role in genetic instability, promotes variable epigenetic instability throughout the epigenome.

doi:10.1371/journal.pgen.1006900

作者:何向伟 点击:

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