Identification of novel PPARγ target genes in primary human adipocytes
Identification of novel PPARγ target genes in primary human adipocytes
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DOI：
10.1016/j.gene.2005.10.021
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发表时间：
2006-03-15
期刊：
影响因子：
3.5
通讯作者：
Dean, NM
中科院分区：
文献类型：
--
作者：
Perera, RJ;Marcusson, EG;Dean, NM
成脂是指未分化的前体细胞分化为富含脂肪的脂肪细胞的过程。核蛋白过氧化物酶体增殖物激活受体(PPAR)在脂肪细胞分化中起核心作用。这项研究的目的是识别新的PPAR伽马反应基因，并确定它们在调节人类脂肪细胞分化中的作用。Affymetrix对人类脂肪细胞基因表达的分析发现，在诱导分化后，约有1000个基因显著上调。使用一种新的、经过化学修饰的反义寡核苷酸，在诱导分化之前降低了PPARγ的表达。Affymetrix微阵列对这些细胞的分析确定了278个在统计上显着下调的基因。8个基因在其上游核苷酸(启动子)序列中发现含有PPAR伽马识别元件(PPRE)。这些基因中有四个是新的，以前还没有被描述过。染色质免疫沉淀实验证实了PPAR-γ与其中三个基因的PPRE结合。其中一个基因的同源基因，假想蛋白Flj 20920，此前已被报道参与控制秀丽线虫的体脂组成。抑制该蛋白的表达也会抑制人类脂肪细胞的分化。利用MAST/MEME算法分析下调基因亚集转录本5‘上游区域的新的常见序列基序，并根据其序列相似性进行分组。确定了一些簇，其中最大的簇包含来自26个基因的类似基序，文献支持26个基因中的7个参与脂肪酸代谢或PPAR伽马相互作用。(C)2005年Elsevier B.V.所有权利重新生效。
Adipogenesis is the process by which undifferentiated precursor cells differentiate into fat laden adipocytes. The nuclear proteins peroxisome proliferator-activated receptors (PPARs) play a central role in adipocyte differentiation. The goals of this study were to identify novel PPAR gamma responsive genes and to determine their role in regulating human adipocyte differentiation. Affymetrix profiling of gene expression in human adipocytes identified about 1000 genes that were significantly up-regulated subsequent to induction of differentiation. PPAR gamma expression was reduced prior to induction of differentiation using a novel, chemically modified antisense oligonucleotide. Affymetrix microarray profiling of these cells identified 278 statistically significantly down-regulated genes. Eight genes were found to contain previously documented PPAR gamma recognition element (PPRE) in their upstream nucleotide (promoter) sequence. Four of these genes are novel and have not previously been characterized. Chromatin immuno-precipitation experiments confirmed the binding of PPAR gamma to the PPRE of three of these genes. The ortholog of one of these genes, hypothetical protein FLJ 20920, has previously been reported to be involved in the control of body fat composition in Caenorhabditis elegans. Inhibition of expression of this protein was found to also inhibit differentiation of human adipocytes. MAST/MEME algorithm analysis was used to identify novel commonly occurring sequence motifs in the 5' upstream region of transcripts for subset of downregulated genes, which were grouped according to their sequence similarities. A number of clusters were identified and the largest cluster contained similar motifs from 26 genes with the literature supporting 7 of the 26 genes as being involved in fatty acid metabolism or PPAR gamma interaction. (C) 2005 Elsevier B.V. All rights resserved.