EFRI CEE: Human cardiac opto-epigenetics with HDAC inhibitors

对疾病的易感性和对药物的反应仅部分取决于我们的遗传密码。DNA在细胞核中的组织、包装和微妙的动态相互作用可以深刻地改变基因表达并影响人类健康。DNA包装和动力学可以被称为基因表达的表观遗传修饰剂的因子和分子改变，并且在肿瘤学和心脏病学中具有极大的兴趣。该EFRI项目的总体目标是更好地了解心脏细胞中动态染色质修饰剂的作用，以激发肿瘤学和心脏病学交叉领域的新疗法，并帮助开发更安全，更有效的药物。该团队将部署新的光学技术和光敏工具来应对这一挑战。 组蛋白去乙酰化酶抑制剂（HDACi）代表一类强大的染色质修饰剂。HDACi作为治疗剂的积极开发已经产生了500多种小分子，目前处于临床试验的不同阶段。该团队将利用HDAC介导的染色质结构控制的一个关键特征，即与其他抑制性染色质调节剂相比，其快速动力学和可逆性。他们将开发一种新的框架和技术，将表观遗传调节与表型联系起来，并将其应用于受到环境压力的人类干细胞衍生的心肌细胞。光开关小分子（HDACi）和图案化光用于在时空中压印动态表观遗传修饰。光学门控高压冷冻将通过电子显微镜成像，对立即HDACi介导的染色质调节进行时间分辨的精确配准。记录由细胞功能的表观遗传主调节因子触发的事件序列将对生物功能的基本理解产生广泛的影响，即基因组重排如何与不同压力下的表型联系起来。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响评审标准进行评估来支持。

Predisposition to disease and reaction to drugs only partially depend on our genetic code. The organization, packing and subtle dynamic interactions of the DNA in the cell nucleus can profoundly modify gene expression and affect human health. The DNA packing and dynamics can be altered by factors and molecules known as epigenetic modifiers of gene expression and are of great interest in oncology and cardiology. The overall goal in this EFRI project is to obtain better understanding of the action of the dynamic chromatin modifiers in heart cells to inspire new therapies at the intersection of oncology and cardiology and help develop safer and more effective drugs. The team will deploy new optical techniques and light-sensitive tools to address this challenge. Histone deacetylase inhibitors (HDACi) represent a class of powerful chromatin modifiers. Active development of HDACi as therapeutic agents has yielded over 500 small molecules, currently at different stages of clinical trials. The team will leverage a key feature of HDAC-mediated control of the chromatin structure, namely its fast dynamics and reversibility compared to other repressive chromatin regulators. They will develop a new framework and technology for linking epigenetic modulation to phenotype, and apply it to human stem-cell-derived cardiomyocytes subjected to environmental stressors. Photoswitchable small molecules (HDACi) and patterned light are used to imprint a dynamic epigenetic modification in time-space. Optically-gated high-pressure freezing will temporally-resolved precise registration of the immediate HDACi-mediated chromatin modulation, imaged by electron microscopy. Documenting the sequence of events, triggered by the epigenetic master-regulators of cell function, will have a broad impact for fundamental understanding of biological function, namely how does the genome re-arrangement link to phenotype under different stressors.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.