大鼠和小鼠基因转录调控的顺式反式作用机制研究

基因转录在生物进化历程中起着十分关键的作用。早在四十多年前,美国的进化论生物学家King和Wilson就认为人与黑猩猩之间在生物大分子结构上的差别微乎其微,并不能说明二者之间在外表形态、生物特征和行为等各方面所产生的重大区别，从而提出可能是基因转录调控的改变造成人和黑猩猩的不同。然而有关基因转录调控进化的直接实验证据明显不足。近年来，随着实验手段和生物信息工具的发展，使得国内外研究学者可以开展这方面的研究，其中，杂交模型是一种经典的可用于区分基因转录调控因素中顺式调控元件（cis elements）和反式作用因子（trans factors）作用大小的研究模型。因此，通过杂交模型研究基因转录调控的顺式作用和反式作用对理解物种分子表型层面的进化有重要意义。

结合上述研究背景，本论文以大鼠和小鼠融合细胞以及杂交小鼠为研究模型，以转录组测序技术RNA-seq、染色质开放性测序技术ATAC-seq和蛋白与DNA互作技术ChIP-seq等高通量测序技术作为研究手段，开展了三个层面的研究：顺式反式调控相互作用的研究、单独顺式调控的研究以及单独反式调控的研究。

在顺式反式调控相互作用的研究层面，通过分析大鼠和小鼠在基因表达层面和染色质开放性层面顺式反式调控的区别以及遗传模式的变化，发现在基因表达调控层面，更多的基因受到了顺式和反式的共同调控，而在染色质开放性调控层面，更多基因的调控模式是保守的。此外，在遗传模式方面，发现基因表达的遗传呈现出更多不兼容的现象，相反，染色质开放性的遗传则主要表现出保守型的现象。

在单独顺式调控元件的研究层面，通过分析单等位基因在不同组织中的分布变化规律，发现单等位基因在基因表达层面和染色质开放性层面都受到明显的组织细胞特异性调控，进一步发现基因启动子区域的染色质开放性不是形成单等位基因表达的充分条件。

在单独反式作用因子研究层面，通过多物种全基因组转录因子氨基酸序列的比对分析，发现小鼠CDX2蛋白在DNA结合区域有3个特异的氨基酸突变，进一步通过功能性实验分析研究了CDX2蛋白在大鼠和小鼠中介导的转录调控差异以及小鼠CDX2蛋白三个特异氨基酸突变引起的功能变化，结果发现小鼠CDX2和大鼠CDX2之间没有明显的功能差异，但是三个氨基酸单独和组合突变会造成功能的部分缺失。

综上所述，本论文系统地探讨了大鼠和小鼠基因转录调控的进化模式，详细地研究了顺式调控元件和反式作用因子在大鼠和小鼠进化过程中发挥的作用，同时探究了多组学相互结合的应用范畴，发现了哺乳动物物种间即大鼠和小鼠之间不同于低等动物的进化调控模式，即顺式调控的影响并没有显著增多；同时，也发现了单等位基因是受到明显的组织特异性调控；此外，进化上特别保守的转录因子如CDX2也会存在氨基酸的突变，而受到如此强烈正向选择的氨基酸突变并没有在物种中引起功能性的差异。

总之，本论文为顺式反式进化调控的研究打下了良好的基础并提供了可借鉴的思路和方法，其中，大鼠和小鼠融合细胞的研究为哺乳动物物种间顺式反式进化调控的研究开辟了新的思路，后续可以通过类似的研究手段克服生殖隔离的缺陷，进而为探索人类和其他物种进化调控的差异提供可能；杂交小鼠单等位基因的研究为寻求新的常染色体单等位基因提供了有效的研究手段，也为寻求新的印记基因提供了可能；CDX2转录因子的研究为反式作用因子中蛋白氨基酸序列突变导致的进化差异的研究提供了方法参考和借鉴。

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