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The role of DNA replication timing in the establishment of gene expression and chromatin organisation patterns

DNA 复制计时在建立基因表达和染色质组织模式中的作用

基本信息

批准号：
1943901
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1943901
关键词：
role DNA replication timing establishment

项目摘要

Eukaryotic DNA is duplicated according to an evolutionary conserved temporal pattern, meaning that different genomic regions are replicated at different times during S-phase. This temporal pattern of DNA replication is altered during development and differentiation and can be dysregulated in cancers. While temporal changes in genome duplication are associated with altered transcription and chromatin organisation, it is still unknown whether DNA replication timing is a cause or consequence of cellular fate changes.We are using budding yeast to conditionally perturb DNA replication timing genome-wide, combined with genome-wide and targeted molecular and genetic approaches, to address what is the effect of this perturbation in gene expression and chromatin conformation. Using this approach we have identified many differentially expressed (DE) genes and genes with alterations in their chromatin landscape. Among these are meiotic genes, which shouldn't be expressed as our experiments were performed in haploid cells and the diploid stage of the yeast life cycle is the only one that can undergo meiosis. This observation supports the hypothesis that replication timing is important to regulate cellular differentiation. Moreover, by analysing published ChIP datasets we identified an enrichment for the binding of Ume6, a regulator of meiotic genes, among our DE genes. These results suggest that perturbations in the temporal order of DNA replication perturb transcription-factor binding dynamics. Therefore, we are currently analysing transcription-factor binding dynamics genome-wide using our conditional system.Our results show that global changes in replication timing have a genome-wide effect in transcription and chromatin organisation. We are currently exploring the mechanism behind these changes, and hope to increase our understanding of replication timing control of gene expression. A comprehensive analysis of alterations in the genome during cellular division will be of major importance for understanding the mechanisms regulating cell fate changes during differentiation and development.

真核生物的DNA是按照进化保守的时间模式复制的，这意味着不同的基因组区域在S期的不同时间复制。这种DNA复制的时间模式在发育和分化过程中发生改变，并且可能在癌症中失调。虽然基因组复制的时间变化与转录和染色质组织的改变有关，但DNA复制时间是细胞命运变化的原因还是结果仍然未知。我们使用芽殖酵母在全基因组范围内有条件地干扰DNA复制时间，结合全基因组范围和靶向分子和遗传方法，以解决这种扰动对基因表达和染色质构象的影响。使用这种方法，我们已经确定了许多差异表达（DE）基因和基因的染色质景观的改变。其中包括减数分裂基因，这些基因不应该表达，因为我们的实验是在单倍体细胞中进行的，而酵母生命周期的二倍体阶段是唯一可以进行减数分裂的阶段。这一观察结果支持了复制时机对调节细胞分化很重要的假设。此外，通过分析已发表的ChIP数据集，我们确定了我们DE基因中减数分裂基因调节因子Ume6结合的富集。这些结果表明，扰动的时间顺序的DNA复制扰动转录因子结合动力学。因此，我们目前正在分析转录因子结合动力学全基因组范围内使用我们的条件system.Our结果表明，全球复制时间的变化有一个全基因组的转录和染色质组织的影响。我们目前正在探索这些变化背后的机制，并希望增加我们对基因表达的复制时序控制的理解。全面分析细胞分裂过程中基因组的变化，对于理解细胞分化和发育过程中调控细胞命运变化的机制具有重要意义。