C/EBPb and heterochromatin: their role in adipogenesis

描述（由申请人提供）：肥胖是世界上最普遍的健康问题之一，特别是如果考虑到相关疾病（如II型糖尿病、血脂异常和高血压）患病率的增加。肥胖是脂肪细胞大小增加以及新脂肪细胞发育的结果。脂肪生成是一系列遗传事件的结果，其中CCAAT/增强子结合蛋白（C/EBP）起着关键作用。小鼠中C/EBP 2、C/EBP 4或C/EBP 1基因的破坏导致脂肪组织发育缺陷。在脂肪形成过程中，发生特定基因子集的激活和其余基因的沉默。当基因沉默时，染色质浓缩的程度增加，DNA的延伸区域以转录非活性形式包装：异染色质。基因组织成异染色质是控制其沉默的机制之一。有趣的是，C/EBP 2在激素刺激后迅速重新定位在异染色质中。C/EBP 2、C/EBP 4和C/EBP 1在诱导前脂肪细胞分化为脂肪细胞时也集中在异染色质中。我们推测，C/EBP 2可能在细胞分化过程中的基因沉默的调节中发挥作用。因此，本项目的具体目标是在前脂肪细胞和脂肪形成过程中研究：a）调节C/EBP 2同源二聚体和异源二聚体形成的机制，B）控制C/EBP 2亚核分布的机制，以及c）通过确定C/EBP 2靶基因相对于异染色质的位置来研究C/EBP 2在基因表达中的作用。我们的研究将提供深入了解的机制，控制C/EBP的核再分配和他们的作用异染色质核隔室。提高我们对脂肪形成的理解是很重要的，因为它最终将有助于开发肥胖和相关疾病的新治疗策略。这项研究扩展了Piwien-Pilipuk博士在Schwartz博士实验室担任博士后实习生时发起的新方法。现在Piwien-Pilipuk博士已经回到阿根廷并正在建立一个独立的实验室，这些PI通过拟议项目之间的合作互动，包括Piwien-Pilipuk博士和至少一名她的研究生在该项目期间访问Schwartz博士的实验室，将促进Piwien-Pilipuk博士的职业发展，除了通过合作论文增加对C/EBP β调节的理解之外。这项研究将主要在阿根廷布宜诺斯艾利斯的Leloir研究所进行，作为NIH授予Schwartz博士的R 01 DK 46072号基金的延伸。公共卫生相关性：肥胖是世界上最普遍的健康问题之一，特别是如果考虑到与糖尿病等相关疾病。提高我们对脂肪形成的理解将最终有助于肥胖和相关疾病的新治疗策略的发展。

DESCRIPTION (provided by applicant): Obesity is one of the most prevalent health problems in the world, particularly if it is considered in relation to the increase in prevalence of associated diseases such as type II diabetes, dyslipemia and hypertension. Obesity is the consequence of increased adipocyte size as well as development of new fat cells. Adipogenesis results from a cascade of genetic events in which CCAAT/Enhancer Binding proteins (C/EBPs) play a key role. Disruption of the C/EBP2, C/EBP4 or C/EBP1 gene in mice causes defective development of adipose tissue. During adipogenesis the activation of a specific subset of genes and silencing of the remainder takes place. As genes are silenced, the extent of chromatin condensation increases, and extended regions of DNA are packaged in transcriptionally inactive form: heterochromatin. The organization of genes into heterochromatin is one of the mechanisms that control its silencing. Intriguingly, C/EBP2 rapidly relocalizes in heterochromatin upon hormonal stimulation. C/EBP2, C/EBP4 and C/EBP1 also concentrate in heterochromatin upon induction of preadipocytes to differentiate into adipocytes. We hypothesize that C/EBP2 may play a role in the regulation of gene silencing during cellular differentiation. Thus the specific aims of this project are to investigate in preadipocytes and during adipogenesis: a) mechanisms that regulate the formation of homo- and heterodimers of C/EBP2, b) mechanisms that control the subnuclear distribution of C/EBP2, and c) the role of C/EBP2 in gene expression by determining the position of C/EBP2 target genes with respect to heterochromatin. Our studies will provide insight into the understanding of the mechanism that controls the nuclear redistribution of C/EBPs and their role in the heterochromatic nuclear compartment. Improvement of our understanding of adipogenesis is important, for it will ultimately contribute to the development of new therapeutic strategies for obesity and related disorders. This study extends new approaches initiated by Dr. Piwien-Pilipuk when she was a postdoctoral trainee in Dr. Schwartz's lab. Now that Dr. Piwien-Pilipuk has returned to Argentina and is establishing an independent lab, the collaborative interactions between these PI's through the proposed project, involving visits to Dr. Schwartz's lab by Dr. Piwien-Pilipuk and at least one of her graduate students during the course of this project, will facilitate Dr. Piwien-Pilipuk's career development, in addition to adding to understanding of the regulation of C/EBP beta through collaborative papers. This research will be done primarily at Instituto Leloir, Buenos Aires, Argentina as an extension of NIH Grant R01DK46072 to Dr. Schwartz PUBLIC HEALTH RELEVANCE: Obesity is one of the most prevalent health problems in the world, particularly if it considered in relation to associated diseases such as diabetes. Improvement of our understanding of adipogenesis will ultimately contribute to the development of new therapeutic strategies for obesity and related disorders.