Multiprotein complexes in gene repression

DNA结合蛋白调节基因表达以协调我们的发育和生理。这些蛋白质通过识别靶基因中的特定控制序列并打开或关闭这些基因来运作。人工调节特定基因来治疗某些遗传性疾病是可能的。遗传性血红蛋白病是世界上最常见的遗传性疾病之一。成人β血红蛋白基因的突变会导致镰状细胞贫血和β地中海贫血等疾病。这些疾病可能会严重削弱或致命，往往需要终身治疗。目前的治疗（如反复输血和随后的铁螯合疗法）对患者要求很高，价格昂贵，并且从长远来看可能无效。未来提出的治疗方法包括重新激活通常沉默的血红蛋白基因（如胎儿血红蛋白），以弥补成人β血红蛋白的缺失。我们一直在研究一种称为BKLF的DNA结合蛋白。我们已经证明了BKLF关闭基因，特别是我们已经证明了使用哺乳动物模型系统，BKLF关闭胎儿血红蛋白基因。因此，抑制BKLF作用成为一个重要的目标，因为这可能导致胎儿血红蛋白的重新激活，以减轻镰状细胞贫血和β地中海贫血。我们正在寻求了解BKLF沉默基因表达的分子机制，以确定其他蛋白质与它的操作，并定义其活动，在努力确定抑制BKLF的行动的最佳途径。最后，研究定义的模型基因，如血红蛋白基因应阐明基因调控的一般原则，可能是有用的控制基因表达在其他治疗或实验环境。

DNA-binding proteins regulate gene expression to co-ordinate our development and physiology. These proteins operate by recognizing specific control sequences in target genes and turning these genes on or off. It may be possible to artificially regulate specific genes to treat certain inherited disorders. One of the most common genetic diseases worldwide is inherited haemoglobinopathy. Mutations in the adult beta haemoglobin gene cause diseases such as sickle cell anaemia and beta thalassaemia. These diseases can be seriously debilitating or lethal and often require lifelong treatment. Current treatments (such as repeated blood transfusion and subsequent iron chelation therapy) are demanding on the patient, expensive, and in the long run can be inneffective. Proposed future treatments involve reactivating normally silent haemoglobin genes (such as foetal haemoglobin) to compensate for the absence of adult beta haemoglobin. We have been studying a DNA-binding protein termed BKLF. We have shown that BKLF turns genes off and in particular we have shown using mammalian model systems that BKLF turns off the foetal haemoglobin gene. Inhibiting BKLF action therefore becomes an important goal, as this might lead to a reactivation of foetal haemoglobin to alleviate sickle cell anaemia and beta thalassaemia. We are seeking to understand the molecular mechanisms by which BKLF silences gene expression, to identify other proteins with which it operates, and to define their activities, in an effort to identify the best ways of inhibiting BKLF's action. Ultimately, studies on defined model genes such as the haemoglobin genes should elucidate general principles of gene regulation that may be useful in controlling gene expression in additional therapeutic or experimental contexts.