Spatial changes in gene organization during adipogenesis

描述(申请人提供)：肥胖和与肥胖相关的健康并发症，包括糖尿病，影响了美国相当大比例的人口，预测表明，肥胖和超重的人数未来将继续上升。由于肥胖和相关并发症造成的身体和心理社会问题，加上相关的生产力损失，医疗保健费用令人震惊。虽然有必要改进策略，以改变肥胖和超重人群的生活方式，但必须继续进行基础研究，以了解调节体重增加的生理过程。人们在识别在脂肪组织形成过程中被激活的基因、研究它们的功能以及确定这些基因表达的调控机制上付出了相当大的努力。识别促进脂肪生成的分子可能会继续导致以一种对肥胖和肥胖相关疾病的治疗有用的方式调节脂肪生成的策略的发展。然而，最近开发的方法学导致了一个新兴的研究领域，它不仅关注单个基因的调节，而且允许分析任何感兴趣的生物过程中涉及的基因的三维结构。我们的初步研究表明，在成脂分化开始后不久，在成脂过程中表达的基因在三维空间中物理上相互关联，尽管它们位于不同的染色体上，并且在分化前没有接触。这种基因关联或聚集是在脂肪形成过程中发生的一种以前没有特征的事件。PI和共同的PI开发了导致这一发现的方法学，现在寻求进一步表征脂肪形成过程中的基因聚集，调查其功能相关性，并确定导致其发生或发生所需的因素。我们设想，最终，我们的研究和其他性质相似的研究将导致定义控制基因表达和细胞分化的新过程，并识别先前未知的调节这些过程的分子。此外，我们认为这些分子可能代表了药物设计和筛选的一类全新的靶点。肥胖和与肥胖相关的健康并发症，包括糖尿病，在美国影响着相当大一部分人口。虽然有必要改进策略，改变肥胖和超重人群的生活方式，但必须继续进行基础研究，以了解调节体重增加的生理过程。我们发现，在脂肪细胞形成过程中表达的基因在三维空间中是物理上相互关联的，尽管它们位于不同的染色体上，并且在脂肪细胞分化之前没有接触过。这种基因关联或聚集是在脂肪形成过程中发生的一种以前没有特征的事件。基因聚集的进一步特征可能导致定义控制基因表达和细胞分化的新过程，并识别先前未知的调节这些过程的分子。这些分子可能代表了未来治疗的一种全新的靶点。

DESCRIPTION (provided by applicant): Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the U.S., 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, are staggering. While it is necessary to improve strategies that will result in lifestyle changes among the obese and overweight population, basic research toward understanding the physiological processes regulating weight gain must be continued. Considerable effort has been placed on identifying genes that are turned on during the formation of adipose tissue, investigating their function, and determining the mechanisms by which the expression of these genes are regulated. Identification of molecules that contribute to adipogenesis will likely continue to lead to the development of strategies to modulate adipogenesis in a manner that is useful for the treatment of obesity and obesity related disease. However, recently developed methodologies have led to an emerging field of research that does not simply focus on the regulation of individual genes but instead permits analysis of the three-dimensional structure of genes involved in any biological process of interest. Our initial studies reveal that shortly after the onset of adipogenic differentiation, genes that will be expressed during adipogenesis are physically associated with each other in three-dimensional space despite the fact that they are located on different chromosomes and were not in contact prior to differentiation. This gene association, or clustering, is a previously uncharacterized event that occurs during adipogenesis. The PI and the co-PI, who developed the methodologies that led to this discovery, now seek to further characterize gene clustering during adipogenesis, investigate its functional relevance, and identify factors that contribute to or are required for its occurrence. We envision that ultimately our studies and others that are similar in nature will result in the definition of new processes controlling gene expression and cellular differentiation and in the identification of previously unknown molecules that mediate these processes. Furthermore, we propose that such molecules may represent an entirely new class of targets for drug design and screening. Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the U.S. While it is necessary to improve strategies that will result in lifestyle changes among the obese and overweight population, basic research toward understanding the physiological processes regulating weight gain must be continued. We have discovered that genes that will be expressed during the formation of fat cells are physically associated with each other in three-dimensional space despite the fact that they are located on different chromosomes and were not in contact prior to fat cell differentiation. This gene association, or clustering, is a previously uncharacterized event that occurs during adipogenesis. Further characterization of gene clustering may result in the definition of new processes controlling gene expression and cellular differentiation and in the identification of previously unknown molecules that mediate these processes. Such molecules may represent an entirely new class of targets for future therapies.