The prevalence of obesity is astounding, and obesity-related health care costs amount to more than $147 billion a year in the US. Adipocytes in adipose tissue play a major role in obesity, as adipocytes are responsible for storing excess fat. Our lab previously found that the arginine methyltransferase Prmt5 is required for adipocyte differentiation, in part due to its ability to mediate enhancer-promoter loops, cis- interactions between transcribed genes on the same chromosome, and trans-interactions between adipocyte- specific regulatory sequences on different chromosomes. A major goal of this study is to identify how Prmt5 mediates higher order chromatin interactions genome-wide and whether this corresponds to transcriptional activation prior to and during adipogenesis. An additional aim is to establish whether transcription factor Sp2 and other proteins associate with Prmt5 to aid in Prmt5?s ability to act as a transcriptional activator in preadipocytes. To test this, I will investigate Prmt5?s chromatin binding sites genome-wide prior to and during adipogenesis and relate it to chromatin conformation changes with and without Prmt5 knockdown. I will utilize high-level computational approaches to draw conclusions by integrating my chromatin landscape and genome organization studies with publicly available datasets in the adipogenic model, the 3T3-L1 cell line. The study will also investigate Sp2 and Prmt5 complexing partners and whether Sp2 is an important coregulator of Prmt5-target genes during adipogenesis. These studies will provide critical insight into how Prmt5 and other factors regulate the chromatin landscape, higher order chromatin structure and transcriptional activation during adipogenesis. My studies will shed light on this relatively understudied protein arginine methyl transferase and may lead to identification of novel therapeutic targets for modulating adipogenesis and targeting obesity and obesity-related diseases. .
The health effects related to being overweight or obese are a major economic burden in the US. A better understanding of adipogenesis, the differentiation of preadipocytes to fat-storing adipocytes, is needed to combat the excess fat storage observed with obesity in adipose tissue. This study will investigate the molecular functions of an arginine methyl transferase in preadipocytes prior to and during differentiation, which may uncover a novel therapeutic target for combating obesity and obesity-related diseases.
