人和小鼠基因内含子参与转录调控的计算研究

Transcriptional regulation is a key process in eukaryotic gene expression. Innumerable studies have focused on the canonical promoter, located upstream from the transcriptional start site. Recent laboratory and computational results suggest that there are transcriptional regulatory elements in introns, particularly in the first introns. However, the present studies on the role of introns in controlling gene transcription are still in an initial stage, and the transcriptional regulatory elements underlying in introns and their natures are not very clear. For these reasons, we plan to perform a systemic research on the relationships between introns and transcriptional regulation. Using the genomic data in humans and mice, we will first carry on computational analyses about the characteristics of intron sequences and evaluate the potential that the introns are likely to be involved in transcriptional regulation. Then using some statistical methods,we will recognize the transcriptional regultory elements in introns and examine their distributions in corresponding target sequences contexts. Finally, we will develop the mathematical models to identify the cooperative regulatroy elements in defined intron-containing promoters and infer the transcriptional synergy between introns and other regions. Based on that, we will explore the intronic mechanisms in transcriptional regulation. Meanwhile,we will also construct the network between interacting transcriptional factors in human and mouse genes including introns. In addtion, we will study the elvolutional features of introns from the insight of transcriptional regulation through comparing the charateristics of the transcriptional regulatory elements in orthologous genes between humans and mice. For obtaining systermatic results, the complexity of introns, such as alternative splicing, will be fully considered. The expected results of this study will be helpful for understanding the biological functions of introns from a new viewpoint, as well as for extending the region of research on gene transcriptional regulation.

转录调控是真核基因表达调控的重要环节，关于基因转录调控的研究主要集中在转录起始位点上游区域（典型启动子区域）。近期的实验和计算分析表明，一些基因的内含子中也含有转录调控元件，然而目前对基因尤其是哺乳动物基因内含子转录调控相关功能的研究还处于探索阶段，对内含子中包含的转录调控元件、性质及其参与转录调控的方式尚不清楚。鉴于此，本项目拟以人和小鼠基因作为研究对象，分析内含子序列特征，探索内含子参与转录调控的可能性；利用统计方法识别人和小鼠基因内含子中的转录调控元件，并对元件在目标序列上的分布特征进行分析；发展计算模型预测人和小鼠基因中的转录调控模块，研究内含子与其他区域的转录协同作用，探索内含子参与转录调控的主要方式，并依此构建转录因子相互作用网络；对人和小鼠同源基因内含子中的调控元件进行比较，从转录调控角度研究内含子进化规律。本课题将从新的角度研究内含子的功能，并拓展基因转录调控研究的领域。

转录调控是真核基因表达调控的重要环节，关于基因转录调控的研究主要集中在转录起始位点上游区域(典型启动子区域)。实验和计算分析表明，一些基因的内含子中也含有转录调控元件，然而对基因尤其是哺乳动物基因内含子转录调控相关功能的研究还处于探索阶段，对内含子中包含的转录调控元件、性质及其参与转录调控的方式尚不清楚。本研究以人和小鼠基因为对象，对内含子参与转录调控进行计算分析。 ①利用统计方法提取人管家基因上游至第一内含子序列中潜在的组合转录调控模体，分析模体间的距离、区域分布等特征，探讨内含子参与基因转录调控的可能性及其参与方式。在管家基因中共获得960对潜在转录调控模体对，其中57%与实验已知的具有转录相互作用的因子对吻合，共涉及12组因子对。分析发现超过80%的模体对偏好上游区域及“上游-内含子”区域，且大部分为协同作用。模体在基因转录起始位点附近较为集中，模体对的两个模体之间距离较近，60%左右距离在200bp以内，特别地，65%的模体对特征距离在100bp以内，短距离间隔有利于转录因子间的协同作用。②利用Markov链方法在小鼠核糖体蛋白基因上游至第一内含子序列中抽提出一批高频出现模体，这些模体大部分与TRANSFAC中收集的小鼠基因转录因子结合位点吻合，是潜在的调控元件。将这些模体两两组合，利用超几何分布和Mann–Whitney U检验方法获得了133对潜在转录调控模体对，其中一些与已知具有相互作用的转录因子对吻合，且大部分为协同作用。对抽提的模体对在不同区域中的出现情况进行分析，发现模体对主要出现在“上游-上游”(95.5%)和“上游-内含子”(57.9%)区域。这些研究结果进一步支持了内含子参与转录调控的假设，并且推测高表达基因的上游与内含子之间具有转录协同作用。