This proposal outlines a novel theory for the epigenetic regulation of cardiac development that is based upon strong preliminary data and evolving concepts related to the organization of chromatin within cells. Regions of compacted and silenced heterochromatin reside at the periphery of the cell nucleus in association with the inner nuclear lamina. These lamin associated domains or LADs are dynamic, and change with cellular differentiation. In this proposal, I propose to test whether releasing LADs from the nuclear periphery can result in changes in cardiac differentiation of cardiac precursor cells, and whether tethering of LADs to the nuclear lamina can result in opposing effects. Our preliminary data indicate that Hdac3 plays a non-catalytic role in tethering LADs by functioning in association with Lap2 (an integral nuclear membrane protein) and cKrox (a DNA-binding transcription factor). Further, our work shows that loss of the tethering function of Hdac3 can modulate LADs and accelerate cardiac differentiation. We will explore the function of LADs in the cardiac lineage commitment and the role of LAD tethering complexes. We will identify specific epigenetic marks characteristic of LAD-tethered chromatin and test the function of these marks. Finally, we will characterize the protein complexes that compose LAD tethers. If successful, this work will open a new field of investigation relating to signal transduction cascades and developmental signals that regulate the orchestrated activation of complex gene programs in the cardiovascular system. The findings may elucidate cardiac disorders including cardiomyopathies related to abnormalities of the nuclear lamina (the laminopathies) and will provide new avenues for manipulating and evaluating cardiovascular development.
This proposal will test the hypothesis that cardiac muscle cells are formed by the coordinated activation of gene programs that are otherwise silenced within tightly compacted regions of DNA that are sequestered to the periphery of the nucleus where they are tethered to the nuclear lamina or membrane. Emerging data suggest that this is a novel mechanism of epigenetic regulation that may go awry in some forms of heart failure, including those related to mutations in components of the nuclear membrane that are known as 'laminopathies' and some forms of muscular dystrophy. Understanding how these gene programs are regulated within the 3-dimensional space of the cell nucleus will inform our ability to treat these diseases.
| Epstein, Jonathan A (2018) CELL FATE DETERMINATION IN 3D: REGULATION OF GENE EXPRESSION VIA CHROMATIN INTERACTIONS WITH THE NUCLEAR MEMBRANE. Trans Am Clin Climatol Assoc 129:121-131 |
| Jain, Rajan; Epstein, Jonathan A (2018) Competent for commitment: you've got to have heart! Genes Dev 32:4-13 |
| Poleshko, Andrey; Shah, Parisha P; Gupta, Mudit et al. (2017) Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction. Cell 171:573-587.e14 |
