Jiralerspong S, Patel P I
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030-3411, USA.
Proc Soc Exp Biol Med. 1996 Jun;212(2):116-27. doi: 10.3181/00379727-212-43998.
The hypoxanthine phosphoribosyltransferase (HPRT) locus is a constitutively expressed housekeeping gene characterized by a notably higher level of expression in the mammalian brain. The enzyme it encodes is key to purine salvage in humans and is the basis for the X-linked recessive disorder, Lesch-Nyhan syndrome (LNS). Methylation in the promoter plays a critical, if not fully understood, role in transcriptional silencing of the locus on the inactive chromosome, possibly by conferring structural stability. In vivo footprinting assays of the promoter region have shown protein interaction with multiple Spl-binding sites, a possible AP2 site, and a potentially novel binding site. In vitro studies of HPRT promoter deletion constructs have identified a minimal promoter element necessary for maximal transcription and a position-dependent, orientation-independent repressor element (HPRT-NE) that functions on heterologous promoters. Regulatory intron elements have also been observed. Studies on transgenic mice bearing HPRT promoter constructs have shown that the minimal promoter element is insufficient for in vivo expression and that HPRT-NE is responsible for conferring neuronal specificity. HPRT-mice possess metabolic defects similar to LNS patients, but fail to develop human behavioral abnormalities, perhaps because of species differences in purine metabolism. A neuronal-specific protein complex appears to be necessary for activator function of HPRT-NE, while a ubiquitously expressed complex may be responsible for repression. Sequence analysis Indicates that the latter complex may depend on the multifunctional transcription factor YY1 for binding. A fuller understanding of HPRT gene regulation will hopefully provide insight into the transcriptional mechanisms controlling the expression of housekeeping and brain-specific genes.
次黄嘌呤磷酸核糖转移酶（HPRT）基因座是一个组成性表达的管家基因，其在哺乳动物大脑中的表达水平显著更高。它所编码的酶是人类嘌呤补救途径的关键，也是X连锁隐性疾病莱施-奈恩综合征（LNS）的基础。启动子区域的甲基化在失活染色体上该基因座的转录沉默中发挥着关键作用，尽管其作用机制尚未完全明确，可能是通过赋予结构稳定性来实现的。启动子区域的体内足迹分析显示，蛋白质与多个Spl结合位点、一个可能的AP2位点以及一个潜在的新结合位点相互作用。对HPRT启动子缺失构建体的体外研究确定了最大转录所需的最小启动子元件以及一个位置和方向依赖性的阻遏元件（HPRT-NE），该元件可在异源启动子上发挥作用。还观察到了调控内含子元件。对携带HPRT启动子构建体的转基因小鼠的研究表明，最小启动子元件不足以支持体内表达，而HPRT-NE负责赋予神经元特异性。HPRT基因敲除小鼠具有与LNS患者相似的代谢缺陷，但未出现人类行为异常，这可能是由于嘌呤代谢存在物种差异。一种神经元特异性蛋白质复合物似乎是HPRT-NE激活功能所必需的，而一种普遍表达的复合物可能负责抑制作用。序列分析表明，后一种复合物可能依赖于多功能转录因子YY1进行结合。对HPRT基因调控的更全面理解有望为控制管家基因和脑特异性基因表达的转录机制提供深入见解。
