Temporal recruitment of transcription factors and SWI/SNF chromatin-remodeling enzymes during adipogenic induction of the peroxisome proliferator-activated receptor γ nuclear hormone receptor
Temporal recruitment of transcription factors and SWI/SNF chromatin-remodeling enzymes during adipogenic induction of the peroxisome proliferator-activated receptor γ nuclear hormone receptor
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DOI：
10.1128/mcb.24.11.4651-4663.2004
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
Imbalzano, AN
中科院分区：
文献类型：
--
作者：
Salma, N;Xiao, HG;Imbalzano, AN
过氧化物酶体增殖物激活受体γ（PPARgamma）调节脂肪生成、脂质代谢和葡萄糖稳态，并且该受体在糖尿病、动脉粥样硬化和癌症的发病机制和治疗中的作用已经显现。我们在这里报告，诱导的PPARgamma激活剂和脂肪形成的过度表达的脂肪形成调控蛋白被阻断后，显性负BRG 1或hBRM，不同的SWI/SNF染色质重塑酶的ATP酶亚基的表达。我们证明，组蛋白超乙酰化和C/EBP激活剂，聚合酶II（Pol II），和一般的转录因子（GTF）的结合最初发生在诱导型PPARgamma 2启动子在SWI/SNF功能的情况下。然而，随后在表达显性阴性SWI/SNF的细胞中，聚合酶和GTF从启动子中丢失，解释了PPARgamma 2表达的抑制。为了证实这些数据，我们分析了PPARgamma 2启动子在分化前脂肪细胞中的相互作用。启动子结构的变化，组蛋白超乙酰化，C/EBP激活剂，Pol II和大多数GTF的结合先于SWI/SNF酶与PPARgamma 2启动子的相互作用。然而，PPARgamma 2基因的转录仅发生在随后的关联SWI/SNF和TFIIH与启动子。因此，在脂肪形成过程中，PPARgamma核激素受体的诱导需要SWI/SNF酶来促进起始前复合体的功能。
The peroxisome proliferator-activated receptor gamma (PPARgamma) regulates adipogenesis, lipid metabolism, and glucose homeostasis, and roles have emerged for this receptor in the pathogenesis and treatment of diabetes, atherosclerosis, and cancer. We report here that induction of the PPARgamma activator and adipogenesis forced by overexpression of adipogenic regulatory proteins is blocked upon expression of dominant-negative BRG1 or hBRM, the ATPase subunits of distinct SWI/SNF chromatin-remodeling enzymes. We demonstrate that histone hyperacetylation and the binding of C/EBP activators, polymerase II (Pol II), and general transcription factors (GTFs) initially occurred at the inducible PPARgamma2 promoter in the absence of SWI/SNF function. However, the polymerase and GTFs were subsequently lost from the promoter in cells expressing dominant-negative SWI/SNF, explaining the inhibition of PPARgamma2 expression. To corroborate these data, we analyzed interactions at the PPARgamma2 promoter in differentiating preadipocytes. Changes in promoter structure, histone hyperacetylation, and binding of C/EBP activators, Pol II, and most GTFs preceded the interaction of SWI/SNF enzymes with the PPARgamma2 promoter. However, transcription of the PPARgamma2 gene occurred only upon subsequent association of SWI/SNF and TFIIH with the promoter. Thus, induction of the PPARgamma nuclear hormone receptor during adipogenesis requires SWI/SNF enzymes to facilitate preinitiation complex function.