Causes and functional consequences of chromatin evolution

染色质进化的原因和功能后果

• 批准号: 10551604
• 负责人: Mia Tauna Levine
• 金额: $ 44.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551604
• 关键词: Aging; Biochemistry; Biological; Biology; Cell physiology; Cellular biology; Chromatin; Chromosome Segregation; Complex; Congenital Abnormality; DNA; DNA Packaging; Data; Disease; Drosophila melanogaster; Evolution; Funding; Genes; Genetic; Genome; Genome Components; Genomic Instability; Genomic Segment; Infertility; Investigation; Malignant Neoplasms; Mediating; Modeling; Molecular; Pathway interactions; Proteins; Publishing; Recurrence; Regulation; Research; Resolution; Satellite DNA; Shapes; System; Trisomy; cancer type; chromatin protein; genetic information; genome integrity; hazard; innovation; insight; preservation; protein protein interaction; telomere; virtual

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.

项目摘要 DNA包装到染色质中介导染色体分离、端粒保护和基因组完整性， 以及其他重要的、保守的细胞过程。然而，许多染色质蛋白是惊人的， 未保守的结构域和残基甚至在密切相关的物种之间迅速进化。这个悖论 由快速进化的染色质蛋白支持的保守的染色质依赖性功能表明， 基本的细胞过程需要不断的创新。这种矛盾的生物学意义是贫乏的 我们已经了解，但异常的染色质包装是癌症、不育和衰老的标志。我们 假设染色质蛋白质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。具体来说，我们假设， 染色质蛋白质和DNA重复序列对抗性共同进化：重复DNA进化危及基本 染色质功能，触发染色质蛋白质的相互进化，以恢复这些基本的染色质 功能协调发展的DNA重复序列进化和染色质蛋白质适应的反复发生， 共同进化的物种特异性基因组成分。为了探讨这种对抗性协同进化模型，我们 进行进化引导的功能分析：我们将一个从一个基因组中分离出来的染色质蛋白交换到一个焦点基因组中。 密切相关的物种，产生一个“进化错配”之间的当代DNA重复一个 一个物种和另一个物种的当代染色质蛋白。在交换 转座子沉默蛋白进入果蝇，我们触发了转座子过度增殖， 基因组完整性的丧失。在交换DNA卫星相关蛋白的分歧版本时， 转化为D.在黑腹果蝇中，我们同样引发了基因组完整性的严重丧失，但通过一个独特的途径。 在成功地确定了在当前的环境中参与对抗性共同进化的基因组成分之后， 在这段时间里，我们正准备揭开DNA重复序列危害人类健康的分子机制。 基本的染色质生物学和染色质蛋白减轻这些威胁的分子机制。 利用我们两个已建立的系统，我们将探讨两个系统的进化和功能多样化， 共同进化形成的重要染色质介导的途径：1）染色质可及性的调节， 易受转座子插入影响的基因组区域和2）富含DNA缠结的解析 DNA卫星阵列我们发表的和初步的数据也推动了我们的调查， 共同进化的反响超出了交战双方，引发了次级共同进化动力， 保护蛋白质：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重复进化的其他不可见的危害 并确定适应性进化如何塑造和重塑染色质以保持重要的基因组功能。