Menconi Giulia, Bedini Andrea, Barale Roberto, Sbrana Isabella
Dip. Informatica, Università di Pisa, Largo Pontecorvo, Pisa, Italy; Istituto Nazionale di Alta Matematica "Francesco Severi", Piazzale Aldo Moro, Città Universitaria, Roma, Italy.
Dept. Mathematics and Statistics, The University of Melbourne Victoria, Australia.
PLoS Comput Biol. 2015 Apr 10;11(4):e1004136. doi: 10.1371/journal.pcbi.1004136. eCollection 2015 Apr.
In this study we provide the first comprehensive map of DNA conformational flexibility in Saccharomyces cerevisiae complete genome. Flexibility plays a key role in DNA supercoiling and DNA/protein binding, regulating DNA transcription, replication or repair. Specific interest in flexibility analysis concerns its relationship with human genome instability. Enrichment in flexible sequences has been detected in unstable regions of human genome defined fragile sites, where genes map and carry frequent deletions and rearrangements in cancer. Flexible sequences have been suggested to be the determinants of fragile gene proneness to breakage; however, their actual role and properties remain elusive. Our in silico analysis carried out genome-wide via the StabFlex algorithm, shows the conserved presence of highly flexible regions in budding yeast genome as well as in genomes of other Saccharomyces sensu stricto species. Flexibile peaks in S. cerevisiae identify 175 ORFs mapping on their 3'UTR, a region affecting mRNA translation, localization and stability. (TA)n repeats of different extension shape the central structure of peaks and co-localize with polyadenylation efficiency element (EE) signals. ORFs with flexible peaks share common features. Transcripts are characterized by decreased half-life: this is considered peculiar of genes involved in regulatory systems with high turnover; consistently, their function affects biological processes such as cell cycle regulation or stress response. Our findings support the functional importance of flexibility peaks, suggesting that the flexible sequence may be derived by an expansion of canonical TAYRTA polyadenylation efficiency element. The flexible (TA)n repeat amplification could be the outcome of an evolutionary neofunctionalization leading to a differential 3'-end processing and expression regulation in genes with peculiar function. Our study provides a new support to the functional role of flexibility in genomes and a strategy for its characterization inside human fragile sites.
在本研究中，我们绘制了酿酒酵母完整基因组中DNA构象灵活性的首张综合图谱。灵活性在DNA超螺旋和DNA/蛋白质结合中起关键作用，调控DNA转录、复制或修复。对灵活性分析的特别关注涉及其与人类基因组不稳定性的关系。在人类基因组不稳定区域（定义为脆性位点）中检测到了灵活序列的富集，这些区域的基因定位并在癌症中频繁发生缺失和重排。有人提出灵活序列是脆性基因易断裂的决定因素；然而，它们的实际作用和特性仍然难以捉摸。我们通过StabFlex算法在全基因组范围内进行的计算机分析表明，在芽殖酵母基因组以及其他酿酒酵母属物种的基因组中都存在高度灵活的区域。酿酒酵母中的灵活峰确定了175个映射在其3'UTR上的开放阅读框（ORF），该区域影响mRNA的翻译、定位和稳定性。不同延伸长度的(TA)n重复塑造了峰的中心结构，并与聚腺苷酸化效率元件（EE）信号共定位。具有灵活峰的ORF具有共同特征。转录本的特点是半衰期缩短：这被认为是参与高周转率调节系统的基因所特有的；一致地，它们的功能影响细胞周期调控或应激反应等生物学过程。我们的研究结果支持了灵活峰的功能重要性，表明灵活序列可能源自经典TAYRTA聚腺苷酸化效率元件的扩展。灵活的(TA)n重复扩增可能是进化新功能化的结果，导致具有特殊功能的基因在3'-末端加工和表达调控上存在差异。我们的研究为基因组中灵活性的功能作用提供了新的支持，并为在人类脆性位点内对其进行表征提供了一种策略。
