Multiprotein complexes in gene repression

dna结合蛋白调节基因表达，协调我们的发育和生理。这些蛋白质通过识别目标基因中的特定控制序列并打开或关闭这些基因来运作。通过人为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。这些疾病可使人严重衰弱或致命，往往需要终生治疗。目前的治疗方法（如反复输血和随后的铁螯合治疗）对患者要求很高，费用昂贵，从长远来看可能无效。建议的未来治疗包括重新激活正常沉默的血红蛋白基因（如胎儿血红蛋白）来补偿成人血红蛋白的缺失。我们一直在研究一种叫做BKLF的dna结合蛋白。我们已经证明了BKLF会关闭基因，特别是我们已经用哺乳动物模型系统证明了BKLF会关闭胎儿血红蛋白基因。因此，抑制BKLF的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再激活，以减轻镰状细胞性贫血和地中海贫血。我们正在寻求了解BKLF沉默基因表达的分子机制，确定与之相关的其他蛋白质，并确定其活性，以努力确定抑制BKLF作用的最佳方法。最终，对已定义的模式基因（如血红蛋白基因）的研究应阐明基因调控的一般原则，这可能有助于在其他治疗或实验环境中控制基因表达。

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.