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.
