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.

细胞使用精心制作的系统来确定在发育和分化过程中以及对环境条件和刺激的响应中表达何时何地表达特定基因。该系统以可遗传的表观遗传标记的形式覆盖在DNA上，该标记通过在不改变DNA序列的情况下修改基因组的结构组织来控制基因表达。表观遗传标记可以通过适应染色质（一种形成真核细胞核中形成染色体的DNA/蛋白质复合物）来使其沉默或激活它们，以抑制或刺激基因活性，这可以驱动遗传上相同的细胞与彼此不同。现在有足够的证据表明异常表观遗传调节会导致疾病。但是，与基因突变形成鲜明对比，可以逆转表观遗传学的改变。因此，人们认为，理解人类表观基因组的研究可以导致许多人类疾病（例如癌症，糖尿病和阿尔茨海默氏症）的新型和高效的治疗策略。与目前在文献中使用的相当粗略的数学和计算方法相比，对拟议研究的正式追求将为开发对表观遗传信息的建模，量化和分析的根本不同的方法提供稳固的基础。这可能会对表观遗传学科学领域以及整个医学和社会产生重大影响，这可能会导致新的生物学发现，以理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，通过使用良好的生物学假设和原则性理论和原则性理论和原则性的理论和知识。研究人员将开发用于量化表观遗传随机性的方法，并辨别和分析生物样品之间的表观遗传不一致，从而为研究表观遗传调节在疾病和衰老中的作用提供了新的和令人兴奋的方法。通过将在细胞分裂过程中传输表观遗传信息的过程视为通信系统，引入了甲基化通道的概念，可以以其容量，消散的能量和输入/输出熵来表征。使用实际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性能之间存在着有趣的联系。这表明表观遗传生物学，统计物理学和信息理论的合并可能会导致对正常发育和疾病中表观遗传组和核组织的信息特性之间关系的基本见解。成功完成拟议的工作将改变表观遗传信息的建模，量化和分析的方式，并导致强大的方法论，以理解人类表观基因组的信息理论含量及其在发育，疾病和衰老中的作用。