C/EBPβ 对组蛋白去甲基化酶Kdm5a的转录调控及其在脂肪细胞分化中的功能研究

转录因子C/EBPβ在脂肪发育分化中发挥了重要的作用。我们先前的工作利用ChIP-on-chip技术在3T3-L1脂肪细胞模型中发现了一系列C/EBPβ的潜在靶基因，其中包括组蛋白去甲基化酶Kdm5a。Kdm5a在脂肪细胞发育分化中的作用尚不明确。我们初步的工作发现Kdm5a的表达可能受到C/EBPβ转录激活，并且利用RNAi敲低Kdm5a的表达显著抑制脂肪细胞分化。这提示由C/EBPβ所调控的Kdm5a可能在脂肪细胞分化中发挥重要作用。我们拟利用3T3-L1脂肪细胞模型、腺病毒介导的Kdm5a 敲低或过表达的小鼠以及高脂饮食诱导的肥胖小鼠，结合ChIP-seq、酵母双杂交、串联亲和纯化（TAP）等技术，研究C/EBPβ对Kdm5a的转录调控以及Kdm5a在脂肪细胞分化中的功能和作用机制。该研究将为脂肪细胞分化机理的阐明奠定基础，并可能为防治肥胖及其相关代谢性疾病提供新的药物靶点。

C/EBPβ plays a pivotal role during adipogenesis. In our previous work, a series of potential C/EBPβ target genes were identified in 3T3-L1 adipocytes by using the ChIP-on-chip assays, among which is the H3K4me3 histone demethylase Kdm5a. Although Kdm5a has been reported to be involved in regulating cell proliferation and tumorigenesis, its role in adipogenesis remains poorly understood. Our preliminary experiments indicate that Kdm5a was trans-activated by C/EBPβ and RNAi-mediated knockdown of Kdm5a significantly inhibited adipogenesis, which suggest an important role of Kdm5a in adipogenesis. In this study, we are going to study the transcriptional regulation of Kdm5a by C/EBPβ and explore the role of Kdm5a and its underlying mechanism during adipogenesis in 3T3-L1 adipocyte model, mouse models treated with adeno-virus-mediated shRNA/over-expression and/or high fat diet (HFD) by using ChIP-seq, yeast-two hybrid screening and tandem affinity purification (TAP). Our studies will contribute to the understanding of the mechanism governing adipogenesis and will open up new opportunities for the development of drugs against obesity and related metabolic disorders.