EAGER: Towards Understanding the Information-Theoretic Nature of the Human Epigenome

渴望：了解人类表观基因组的信息理论本质

• 批准号: 1656201
• 负责人: John Goutsias
• 金额: $ 20.08万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656201&HistoricalAwards=false
• 关键词: EAGER; Towards; Understanding; Information; Theoretic

Cells use an elaborate system to determine when and where specific genes will be expressed during development and differentiation as well as in response to environmental conditions and stimuli. This system is overlaid on the DNA in the form of heritable epigenetic marks that control gene expression by modifying the structural organization of the genome without changing the DNA sequence. Epigenetic marks can silence genes or activate them by adapting chromatin (a DNA/protein complex which forms chromosomes within the nucleus of eukaryotic cells) to distinct states that repress or stimulate gene activity and this can drive genetically identical cells to behave differently from each other. There is now ample evidence that aberrant epigenetic regulation can lead to disease. However, and in sharp contrast to gene mutations, epigenetic alterations can be reversed. It is therefore believed that research in understanding the human epigenome can lead to novel and highly effective therapeutic strategies for many human diseases, such as cancer, diabetes, and Alzheimer?s. A formal pursuit of the proposed research will provide a solid foundation for developing fundamentally different methods for the modeling, quantification, and analysis of epigenetic information, as compared to rather crude mathematical and computational methods currently used in the literature. This could potentially have a major impact on the area of epigenetic science, as well as on medicine and society at large, which could lead to new biological discoveries towards understanding the role of epigenetics in development, disease and aging.The main goal of this research is to develop a novel approach for understanding the informational structure and properties of the human epigenome by using well-grounded biological assumptions and principles of statistical physics and information theory. The investigators will develop methods for quantifying epigenetic stochasticity, as well as discern and analyze epigenetic discordance between biological samples, providing new and exciting ways for studying the role of epigenetic regulation in disease and aging. By viewing the process of transmitting epigenetic information during cell division as a communication system, the concept of a methylation channel is introduced, which can be characterized by its capacity, dissipated energy, and input/output entropy. Preliminary results using real epigenetic data have demonstrated an intriguing connection between chromatin organization and informational properties of methylation channels. This shows that a merger of epigenetic biology, statistical physics and information theory may lead to fundamental insights into the relationship between the informational properties of the epigenome and nuclear organization in normal development and disease. Successful completion of the proposed work will transform the way epigenetic information is modeled, quantified, and analyzed, and lead to powerful methodologies for understanding the information theoretic content of the human epigenome and its role in development, disease, and aging.

细胞使用一个复杂的系统来确定特定基因在发育和分化过程中以及对环境条件和刺激的反应中何时何地表达。该系统以可遗传的表观遗传标记的形式覆盖在 DNA 上，通过修改基因组的结构组织而不改变 DNA 序列来控制基因表达。表观遗传标记可以通过使染色质（一种在真核细胞核内形成染色体的 DNA/蛋白质复合物）适应抑制或刺激基因活性的不同状态来沉默基因或激活基因，这可以驱动基因相同的细胞表现出不同的行为。现在有充分的证据表明异常的表观遗传调控可能导致疾病。然而，与基因突变形成鲜明对比的是，表观遗传改变是可以逆转的。因此，人们相信，了解人类表观基因组的研究可以为许多人类疾病（例如癌症、糖尿病和阿尔茨海默病）带来新颖且高效的治疗策略。与目前文献中使用的相当粗糙的数学和计算方法相比，对拟议研究的正式追求将为开发用于表观遗传信息的建模、量化和分析的根本不同的方法奠定坚实的基础。这可能会对表观遗传学领域以及整个医学和整个社会产生重大影响，从而带来新的生物学发现，以了解表观遗传学在发育、疾病和衰老中的作用。这项研究的主要目标是通过使用有根据的生物学假设以及统计物理学和信息论原理来开发一种新的方法来理解人类表观基因组的信息结构和特性。研究人员将开发量化表观遗传随机性的方法，以及辨别和分析生物样本之间表观遗传不一致的方法，为研究表观遗传调控在疾病和衰老中的作用提供新的、令人兴奋的方法。通过将细胞分裂过程中传递表观遗传信息的过程视为一个通信系统，引入了甲基化通道的概念，其可以通过其容量、耗散能量和输入/输出熵来表征。使用真实表观遗传数据的初步结果表明，染色质组织与甲基化通道的信息特性之间存在着有趣的联系。这表明表观遗传生物学、统计物理学和信息论的融合可能会带来对正常发育和疾病中表观基因组信息特性与核组织之间关系的基本见解。成功完成拟议工作将改变表观遗传信息的建模、量化和分析方式，并产生强大的方法来理解人类表观基因组的信息论内容及其在发育、疾病和衰老中的作用。