Dynamic role of Prmt5 in chromatin organization during adipogenesis

肥胖症的流行程度令人震惊，与肥胖症相关的医疗费用总计超过147美元 在美国，每年有10亿美元。脂肪组织中的脂肪细胞在肥胖中起主要作用，就像脂肪细胞一样 负责储存过多的脂肪。我们的实验室先前发现精氨酸甲基转移酶PRMT5是 脂肪细胞分化所必需的，部分原因是它有能力介导增强子-启动子环，顺式-启动子- 同一染色体上转录基因之间的相互作用，以及脂肪细胞之间的反式相互作用- 不同染色体上的特定调控序列。这项研究的一个主要目标是确定PRMT5如何 在全基因组范围内调节高阶染色质相互作用以及这是否对应于转录 成脂前和成脂过程中的激活。另一个目的是确定转录因子Sp2是否 和其他与PRMT5相关的蛋白质帮助PRMT5的S作为转录激活因子的能力 前脂肪细胞。为了验证这一点，我将研究PrMT5‘S染色质结合位点之前和期间全基因组 脂肪生成及其与染色质构象变化的关系，在PRMT5被敲除和不被敲除的情况下。我会利用 通过整合我的染色质景观和基因组得出结论的高级计算方法 组织在成脂模型3T3-L1细胞系中使用公开可用的数据集进行研究。这项研究 还将调查Sp2和PRMT5的络合伙伴，以及Sp2是否是 PRMT5-脂肪形成过程中的靶基因。这些研究将为PRMT5和其他 调节染色质景观、高阶染色质结构和转录激活的因子 成脂作用。我的研究将对这种相对较少被研究的蛋白质精氨酸甲基转移酶和 可能导致发现新的治疗靶点，以调节脂肪生成和靶向肥胖和 与肥胖相关的疾病。 。

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. .