How is expression of the embryonic zeta-globin gene regulated in erythropoiesis?

血红蛋白复合物对生命至关重要，因为它在我们的身体周围运输氧气。血红蛋白由α -珠蛋白、β -珠蛋白和铁组成。在终末分化的红母细胞中维持α -球蛋白与β -球蛋白的相等比例对红细胞的正常产生至关重要。血红蛋白紊乱是由于α -珠蛋白链或β -珠蛋白链产生不足，导致α -珠蛋白与β -珠蛋白比例失衡。这导致产生小的，血红蛋白不足的红细胞和无效的红细胞生成。每年至少有34万名患有严重遗传性血红蛋白疾病的婴儿出生。其中约7万人缺乏α -或β -球蛋白。这些是已知的最常见的单基因疾病，在所研究的所有热带和亚热带人群中，携带率为bb0.1 %。人口动态意味着这现在是一个全球性的健康问题。α -珠蛋白不足最常见的原因是α -珠蛋白基因缺失。症状最严重的儿童患有贫血，并伴有疲乏、呼吸困难和疲劳、脾大（可能疼痛）、黄疸、生长迟缓，许多儿童需要输血。其他并发症包括感染、腿部溃疡、胆结石和叶酸缺乏。在以后的生活中，大多数受严重影响的患者（约85%）都有铁超载，这可能导致肝硬化和心脏问题。本研究的关键点在于，在健康个体和绝大多数α -珠蛋白缺乏症患者中，存在一种替代α -珠蛋白基因，称为ζ -珠蛋白。然而，珠蛋白基因通常只在非常早期的发育中活跃。这项工作的目的是描述ζ -珠蛋白通常沉默的机制，并利用这一信息寻找在患者中重新表达它的新方法。实现珠蛋白的再激活将重新建立血液中α -与β -珠蛋白的重要平衡。这种精准医疗将治愈患有严重地中海贫血及其并发症的人的主要贫血问题，消除输血的需要，提高他们的生活质量。为了了解珠蛋白通常是如何被抑制的，该项目将提供各种高级分子生物学和定量生物信息学技术的培训。细胞培养和基因组工程将用于创建细胞模型，以测试蛋白质因子和基因调控元件对ζ -珠蛋白基因表达的影响。这些模型将通过尖端的基因组学、转录组学和显微镜分析进行检验，这些数据将使用适当的计算方法进行分析。该项目源于与工业界合作伙伴的现有合作，并有可能在未来形成新的合作。

The haemoglobin protein complex is essential for life because it transports oxygen around our bodies. Haemoglobin consists of alpha-globin protein, beta-globin protein and iron. Maintaining an equal ratio of alpha- to beta-globin protein in terminally differentiating erythroblasts is crucial for the normal production of red blood cells. Disorders of haemoglobin result from insufficient production of either the alpha- or beta-globin chains, causing an imbalance in the ratio of alpha- to beta-globin. This leads to production of small, under-haemoglobinised red-cells and ineffective erythropoiesis. At least 340,000 babies with severe genetic disorders of haemoglobin are born each year. Of these ~70,000 suffer from deficiency of the alpha- or beta-globin proteins. These are the most common single gene disorders known, with a carrier rate of >1% among all tropical and subtropical populations studied. Population dynamics mean this is now a global health problem.The most common cause of alpha-globin insufficiency is deletion of the alpha-globin genes. Children with the most severe symptoms suffer from anaemia with associated tiredness, breathlessness and fatigue, a large spleen (which can be painful), jaundice, growth retardation and many require blood transfusions. Other complications include infections, leg ulcers, gall stones and folic acid deficiency. In later life, the majority of severely affected patients (~85%) have iron overload, which can lead to cirrhosis of the liver and heart problems. The critical point for this study is that, in healthy individuals, and the vast majority of patients with alpha-globin deficiency, there is an alternative alpha-globin gene, termed zeta-globin. However, the zeta-globin gene is normally active only in very early development. The aim of this work is to characterise the mechanisms by which zeta-globin is normally silenced and leverage this information to find novel ways of re-expressing it in patients. Achieving zeta-globin reactivation would re-establish the important balance of alpha- to beta- globin proteins in the blood. This precision medicine would cure the primary problem of anaemia for individuals with severe alpha-thalassemia and its attendant complications, removing the need for blood transfusion and improving their quality of life. To understand how zeta-globin is normally repressed, this project will provide training in a variety of advanced molecular biology and quantitative bioinformatic techniques. Cell culture and genome engineering will be used to create cell models that test the effects of protein factors and gene regulatory elements on zeta-globin gene expression. These models will be examined with cutting-edge genomic, transcriptomic and microscopy assays and these data will be analysed using appropriate computational approaches. This project was born out of an existing collaboration with partners in industry and has potential for forming new collaborations in future.