Causes and functional consequences of chromatin evolution

项目总结 DNA包装到染色质中介导了染色体分离、端粒保护和基因组完整性， 在其他基本的、保守的细胞过程中。然而，许多染色质蛋白令人惊讶地 非保守结构域和残基甚至在亲缘关系密切的物种之间也会迅速进化。这一悖论 快速进化的染色质蛋白支持的保守的、染色质依赖的功能表明，一些 基本的细胞过程需要不断的创新。这一悖论的生物学意义很差。 明白，但异常的染色质包装是癌症、不孕不育和衰老的标志。我们 假设染色质蛋白的普遍快速进化是由异常快速的 DNA重复序列的进化，包括转座子和DNA卫星。具体地说，我们假设 染色质蛋白质和DNA重复序列相互对抗地共同进化：重复的DNA进化是必要的 染色质的功能，触发染色质蛋白的相互进化，以恢复这些基本的染色质 功能。反复的DNA重复进化和染色质蛋白适应导致了精致的 共同进化的、物种特有的基因组成分。为了探索这种对抗性的共同进化模式，我们 进行进化引导的功能分析：我们将一个发散的染色质蛋白从一个 亲缘关系密切的物种，在一个物种的当代DNA重复之间产生“进化不匹配” 和另一个物种的当代染色质蛋白。在交换不同版本的 转座子沉默蛋白进入果蝇，我们触发了转座子的过度增殖和 随之而来的是基因组完整性的丧失。在交换DNA卫星相关蛋白的不同版本时 同样，我们也通过一条不同的途径引发了基因组完整性的严重丧失。 已经成功地确定了在当前的 在资助期内，我们现在准备揭开DNA重复危害的分子机制 基本染色质生物学和染色质蛋白减轻这些威胁的分子机制。 利用我们已建立的两个系统，我们将探索两个系统的演变和功能多样化 共同进化形成的重要染色质介导的通路：1)染色质可及性的调节 易受转座子插入的基因组区域和2)富含 DNA卫星阵列。我们公布的和初步的数据也推动了我们对如何对抗的调查 共同进化的影响超出了陷入困境的两方，引发了第二次共同进化动力， 保存蛋白质：多个宿主染色质蛋白之间的蛋白质相互作用。利用转基因技术，细胞生物学， 生物化学和经典遗传学，我们将阐明DNA重复进化的其他看不见的危险 并确定适应性进化如何塑造和重塑染色质，以保护重要的基因组功能。

PROJECT SUMMARY DNA packaging into chromatin mediates chromosome segregation, telomere protection, and genome integrity, among other essential, conserved cellular processes. However, many chromatin proteins are strikingly unconserved—domains and residues evolve rapidly between even closely related species. This paradox of conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that some essential cellular processes require recurrent innovation. The biological significance of this paradox is poorly understood, and yet aberrant chromatin packaging is a hallmark of cancer, infertility, and aging. We hypothesize that the pervasive rapid evolution of chromatin proteins is driven by the exceptionally rapid evolution of DNA repeats, including transposons and DNA satellites. Specifically, we hypothesize that chromatin proteins and DNA repeats antagonistically coevolve: repetitive DNA evolution imperils essential chromatin functions, triggering reciprocal evolution of chromatin proteins to restore these essential chromatin functions. Repeated bouts of DNA repeat evolution and chromatin protein adaptation result in exquisitely coevolved, species-specific components of the genome. To probe this model of antagonistic coevolution, we conduct evolution-guided functional analysis: we swap into a focal genome a diverged chromatin protein from a closely related species, generating an "evolutionary mismatch" between the contemporary DNA repeats of one species and a contemporary chromatin protein of another species. Upon swapping a diverged version of a transposon-silencing protein into Drosophila melanogaster, we triggered transposon hyper-proliferation and a consequent loss of genome integrity. Upon swapping a diverged version of a DNA satellite-associated protein into D. melanogaster, we similarly triggered a profound loss of genome integrity but through a distinct pathway. Having successfully defined the genome components engaged in antagonistic coevolution during the current funding period, we are now poised to unravel the molecular mechanisms by which DNA repeats imperil essential chromatin biology and the molecular mechanisms by which chromatin proteins mitigate these threats. Leveraging our two established systems, we will probe the evolutionary and functional diversification of two vital chromatin-mediated pathways shaped by coevolution: 1) the regulation of chromatin accessibility at genomic regions vulnerable to transposon insertions and 2) the resolution of DNA entanglements enriched in DNA satellite arrays. Our published and preliminary data also propel our investigations of how antagonistic coevolution reverberates beyond the two embattled parties, triggering secondary coevolutionary dynamics that preserve protein:protein interactions among multiple host chromatin proteins. Using transgenics, cell biology, biochemistry, and classical genetics, we will elucidate the otherwise invisible hazards of DNA repeat evolution and determine how adaptive evolution shapes and reshapes chromatin to preserve vital genome functions.