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， 除其他基本配置的蜂窝过程外。但是，许多染色质蛋白都有惊人的 未经保守的 - 域并在密切相关的物种之间迅速保留进化。这个悖论 由快速发展的染色质蛋白支持的保守的染色质依赖性功能表明一些 必需的细胞过程需要经常创新。该悖论的生物学不佳 了解，但异常的染色质包装是癌症，不育和衰老的标志。我们 假设染色质蛋白的普遍快速进化是由异常快速驱动的 DNA重复的演变，包括转座子和DNA卫星。具体来说，我们假设 染色质蛋白和DNA在拮抗过程中重复出现：重复的DNA进化损害必不可少的 染色质功能，触发染色质蛋白的相互进化以恢复这些必需染色质 功能。 DNA重复演化和染色质蛋白适应的重复出现使 基因组的共同发展，特异性成分。为了探究这种拮抗协同进化模型，我们 进行进化引导的功能分析：我们将焦点基因组与A分解的染色质蛋白交换 密切相关的物种，在一个当代DNA重复序列之间产生“进化不匹配” 物种和另一种物种的当代染色质蛋白。交换差异版本的版本 转座子沉默蛋白进入果蝇杂物，我们触发了转座超增殖和A 因此，基因组完整性的丧失。交换DNA卫星相关蛋白的发散版本后 进入D. melanogaster，我们同样通过不同的途径引发了基因组完整性的深刻丧失。 成功定义了在电流期间从事拮抗过程的基因组成分 资金期，我们现在被中毒以揭示DNA重复危险的分子机制 必需的染色质生物学和染色质蛋白减轻这些威胁的分子机制。 利用我们的两个已建立系统，我们将探测两个的进化和功能多样性 通过协同进化形成的重要染色质介导的途径：1）调节染色质的可及性。 基因组区域容易受到转座子插入的影响，2）富集的DNA纠缠的分辨率富含 DNA卫星阵列。我们发布的初步数据也推动了我们对如何对抗的研究 共同进化使两个四面楚歌的政党超越了，触发了次级协同进化动力学 保留蛋白质：多种宿主染色质蛋白之间的蛋白质相互作用。使用转化，细胞生物学， 生物化学和经典遗传学，我们将阐明原本看不见的DNA重复进化的危害 并确定自适应进化的形状和重塑染色质如何保留重要的基因组功能。