The four dimensions of nucleosome chain folding

核小体链折叠的四个维度

• 批准号: 1911940
• 负责人: Sergei Grigoryev
• 金额: $ 113.22万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1911940&HistoricalAwards=false
• 关键词: four; dimensions; nucleosome; chain; folding

DNA in eukaryotic cells is repeatedly coiled around histone proteins forming 'beads-on-a-string' chains of nucleosomes that are further folded into higher-order chromatin structures. Changes in the nucleosome chain packing density and DNA accessibility govern gene expression and repression during cell differentiation and tissue development. This project will investigate the 3-dimensional structures of nucleosome chains in the cell nucleus and their transitions over time in the course of tissue development and maturation, referred to as the 4th dimension. The outcomes of this research will provide crucial information for designing genetic and pharmacological tools capable of altering nucleosome chain folding and thus modulating epigenetic changes and developmental plasticity in differentiated cells and tissues. This project will be deeply integrated with graduate education and provide new research opportunities for undergraduate students, inspiring and training them for careers in STEM.The overall goal of this project is to reveal nucleosome chain folding motifs that characterize certain epigenetic states and are associated with locking down the underlying genes in mature cells and inhibiting tissue regeneration. The first research aim is to resolve the nanoscale chromatin structure of epigenetically distinct chromatin states in a reference human cell line. The second aim is to determine nucleosome chain transitions underlying chromatin condensation during mouse retina development. A unique technique, EMANIC (electron microscopy-assisted nucleosome interaction capture) will be applied to resolve nucleosome folding motifs. This technique will be used in conjunction with biochemical assays to link the nucleosome chain folding with specific epigenetic states and chromatin rearrangements. By integrating crucial structural information: nucleosome repeat length, internucleosomal interactions, and nucleosome chain flexibility with computational modeling, this project will provide new structural cues for engineering chromatin epigenetic states and modifying chromatin functions related to tissue developmental and regenerative processes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

真核细胞中的DNA反复盘绕在组蛋白周围，形成“串珠状”的核小体链，核小体链进一步折叠成高级染色质结构。核小体链堆积密度和DNA可及性的变化控制细胞分化和组织发育过程中的基因表达和抑制。该项目将研究细胞核中核小体链的三维结构及其在组织发育和成熟过程中随时间的转变，称为第四维。这项研究的结果将为设计能够改变核小体链折叠的遗传和药理学工具提供关键信息，从而调节分化细胞和组织的表观遗传变化和发育可塑性。该项目将与研究生教育深度融合，为本科生提供新的研究机会，激励和培训他们从事STEM职业。该项目的总体目标是揭示核小体链折叠基序，这些基序表征某些表观遗传状态，并与锁定成熟细胞中的潜在基因和抑制组织再生有关。第一个研究目标是解析参考人类细胞系中表观遗传学不同染色质状态的纳米级染色质结构。第二个目的是确定小鼠视网膜发育过程中核小体链转换的基础染色质凝聚。一种独特的技术，EMANIC（电子显微镜辅助核小体相互作用捕获）将被应用于解决核小体折叠模体。该技术将与生物化学测定结合使用，以将核小体链折叠与特定的表观遗传状态和染色质重排联系起来。通过整合关键的结构信息：核小体重复长度、核小体间相互作用和核小体链柔性与计算建模，该项目将为染色质表观遗传状态的工程设计和与组织发育和再生过程相关的染色质功能的修改提供新的结构线索。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值进行评估，被认为值得支持和更广泛的影响审查标准。