Lefebvre P, Mouchon A, Lefebvre B, Formstecher P
INSERM U459, Laboratoire de Biochimie Structurale, Faculté de Médecine Henri Warembourg, 1, place de Verdun, 59045 Lille cedex, France.
J Biol Chem. 1998 May 15;273(20):12288-95. doi: 10.1074/jbc.273.20.12288.
The retinoic acid signaling pathway is controlled essentially through two types of nuclear receptors, RARs and RXRs. Ligand dependent activation or repression of retinoid-regulated genes is dependent on the binding of retinoic acid receptor (RAR)/9-cis-retinoic acid receptor (RXR) heterodimers to retinoic acid response element (RARE). Although unliganded RXR/RAR heterodimers bind constitutively to DNA in vitro, a clear in vivo ligand-dependent occupancy of the RARE present in the RARbeta2 gene promoter has been reported (Dey, A., Minucci, S., and Ozato, K. (1994) Mol. Cell. Biol. 14, 8191-8201). Nucleosomes are viewed as general repressors of the transcriptional machinery, in part by preventing the access of transcription factors to DNA. The ability of hRXRalpha/hRARalpha heterodimers to bind to a nucleosomal template in vitro has therefore been examined. The assembly of a fragment from the RARbeta2 gene promoter, which contains a canonical DR5 RARE, into a nucleosome core prevented hRXRalpha/hRARalpha binding to this DNA, in conditions where a strong interaction is observed with a linear DNA template. However, histone tails removal by limited proteolysis and histone hyperacetylation yielded nucleosomal RAREs able to bind to hRXRalpha/hRARalpha heterodimers. These data establish therefore the role of histones NH2 termini as a major impediment to retinoid receptors access to DNA, and identify histone hyperacetylation as a potential physiological regulator of retinoid-induced transcription.
维甲酸信号通路主要通过两种核受体RARs和RXRs来控制。类视黄醇调节基因的配体依赖性激活或抑制取决于维甲酸受体（RAR）/9-顺式维甲酸受体（RXR）异二聚体与维甲酸反应元件（RARE）的结合。尽管未结合配体的RXR/RAR异二聚体在体外能组成性地结合DNA，但已有报道称RARβ2基因启动子中存在的RARE在体内有明显的配体依赖性占据现象（戴伊，A.，米努奇，S.，和小里户，K.（1994年）《分子与细胞生物学》14卷，8191 - 8201页）。核小体被视为转录机制的一般抑制剂，部分原因是它阻止转录因子与DNA接触。因此，研究了hRXRα/hRARα异二聚体在体外与核小体模板结合的能力。来自RARβ2基因启动子的一个片段（包含一个典型的DR5 RARE）组装到核小体核心中，在与线性DNA模板有强相互作用的条件下，阻止了hRXRα/hRARα与该DNA的结合。然而，通过有限蛋白酶解去除组蛋白尾巴和组蛋白超乙酰化产生了能够与hRXRα/hRARα异二聚体结合的核小体RARE。因此，这些数据确定了组蛋白NH2末端作为类视黄醇受体接触DNA的主要障碍的作用，并将组蛋白超乙酰化鉴定为类视黄醇诱导转录的潜在生理调节因子。
