Systems Biology of Epigenetic Mechanisms: How Epigenetics Influences Robustness

Abstract

Robustness, a system's ability to persist characteristic outputs when challenged by perturbations, is an important aspect of biological organisms. Perturbations can come in the form of mutations, environmental conditions (ie temperature), internal conditions (ie age), etc. How organisms achieve robustness, retaining homeostasis in a myriad of situations, is important question in biology and at intrinsically at the root of all therapeutic endeavor.;Epigenetics, heritable changes in gene expression caused by mechanisms other than changes in underlying DNA sequence, include the mechanisms of DNA methylation, chromatin remodeling, transcription factors, RNA interference, etc. Currently little is known about how epigenetics influences robustness. In my thesis I explore how epigenetic mechanisms influence mutational and environmental robustness as well as aging robustness in human beings.;Studies using gene regulatory network models, and corroborated in single-celled organisms, have shown that mutational robustness and environmental robustness are correlated. This correlation constitutes a barrier to the evolution of cell differentiation which requires sensitivity to cues in the extracellular environment during development. To investigate how this barrier might be overcome I extended a gene regulatory network model by adding epigenetic control based generalized function of the Polycomb Group proteins, which evolved in tandem with the transition to multicellularity. Incorporating the epigenetic mechanism allowed decoupling of mutational and environmental robustness, thus allowing the system to be simultaneously robust to mutations while increasing sensitivity to the environment, and promoting cell differentiation.;Aging is the primary risk factor for the most prevalent lethal diseases. Work in model organisms suggests that robustness to age (health span) can be modified by epigenetic mechanisms. One potent epigenetic mechanism that influences aging is microRNA, a short non-translated RNA that causes post-transcriptional repression of target genes. I used a centenarian model of human longevity to determine if miRNA expression contributed to human longevity. I found 39 and 65 differentially expressed miRNA in lymphocytes and serum of centenarians compared to controls respectively. The targets of these miRNA include those in pathways known to affect aging in model organisms, including nutrient signaling and inflammation.