Chromatin is a key determinant of cell phenotype and function. Therefore, chromatin stability over the lifespan is presumably a pre-requisite for maintenance of cell and tissue phenotype and function, and hence healthy aging and longevity. However, chromatin is not a static fixed structure, but is a dynamic and plastic ?breathing? assembly. As a dynamic and plastic entity, chromatin is prone to change or drift, a process likely exacerbated by intrinsic cellular processes and extrinsic/environmental influences. Therefore, this dynamic chromatin likely represents a challenge for a cell to achieve phenotypic stability, healthy aging and longevity, especially for long- lived cells. In other words, given their dynamic chromatin, how do healthy human neurons and cardiomyocytes remain as such for decades? To explain this, we have proposed that cells possess mechanisms of chromatin homeostasis, or chromostasis, that preserve chromatin integrity, suppress phenotypic instability or ?plasticity?, and so slow the pace of aging and promote healthy aging. We will test this hypothesis as follows:
Specific Aim 1. Test whether altered nucleosome stability affects features of chromostasis and cell phenotypic plasticity.
Specific Aim 2. Identify candidate chromostasis genes and small molecule modulators and test their impact on cell phenotypic plasticity.
Specific Aim 3. Test whether enhanced chromostasis promotes healthy aging and longevity. This proposal is broadly significant because it will reveal basic mechanisms of physiological chromatin/epigenetic control and how this impinges on healthy aging and longevity, pathological states such as cell transformation, and therapeutic applications such as cell reprogramming. Accordingly, this proposal can have a major impact on scientific understanding and human health by revealing: 1) mechanisms that underlie stable cell phenotype; 2) biomarkers of age-associated degeneration and predisposition to disease; 3) targets for interventions to promote healthy aging, prevent degenerative disease and cancer, and facilitate therapeutic cell reprogramming.
Healthy aging and longevity depends on maintenance of cell phenotype and function and, in turn, cell type specific epigenetic programs. How cells sustain their epigenetic programs over the lifecourse is not known. We will test the existence of mechanisms of chromatin homeostasis ? ?chromostasis? ? that maintain the epigenome, identify the genes involved and test their contribution to healthy aging.
