Novel Coactivator Functions during Adipogenesis

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 DESCRIPTION (provided by applicant): Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the United States, and projections indicate that the number of obese and overweight individuals will continue to rise in the future. The costs of health care due to the physical and psycho-social problems caused by obesity and related complications, coupled with the associated loss of productivity, is staggering. Improving strategies to induce lifestyle changes among the obese and overweight population is a necessary step toward alleviating this problem, but this approach should be complemented by the development of interventions to control the physiological processes regulating weight gain. Such interventions may include small molecules that modulate regulators of adipose formation and function. Development of such tools will depend upon continued basic research addressing the physiological processes regulating adipogenesis and adipose function. We provide evidence that two enzymes that function as coactivators of adipogenesis, Prmt5 and Jmjd6, drive adipogenesis in a manner that is independent of their catalytic activity. This means that these regulators employ novel and undefined mechanisms to promote adipogenic differentiation. We propose to globally define the functions of these regulators in adipogenesis and to perform structure/function analyses to identify the protein domains that are responsible for the functions that contribute to adipogenesis. The work will address how these regulatory proteins influence both higher-order and local chromatin structure, binding of other regulatory proteins to chromatin, and gene expression. The results of these studies will shed new insight into the regulation of adipogenesis and potentially provide new targets for therapeutic interventions that may be of future use for the treatment of obesity and obesity related disease.