The regulation of globin gene expression during haematopoiesis

我们现在有了整个人类基因组DNA序列的大致图谱。然而，基本的DNA序列只是理解调节基因在正确的时间和正确的细胞类型中产生正确蛋白质的能力的因素之间复杂相互作用的一个起点。我们有一张非常详细的16号染色体区域图。我们希望通过识别序列内的所有基因和调控特征来描述这个区域，然后观察其他（表观遗传）因素，这些因素可以影响基因何时何地变得活跃。DNA在细胞核内与几种蛋白质形成染色质。我们想了解这种染色质是如何在细胞核内排列的，以及什么变化可能是允许基因打开或关闭所必需的。在16号染色体的这个区域有α -珠蛋白基因。这些基因构成血红蛋白分子的一部分，血红蛋白在血液中携带氧气，缺乏血红蛋白会引起贫血，从而导致正常供氧器官的功能障碍。当α -珠蛋白基因以某种方式被破坏时，患者就会患上一种叫做α -地中海贫血的严重贫血。一些患者出生时患有智力低下和其他发育问题以及α地中海贫血——这些患者在我们正在研究的区域中缺少一条16号染色体。根据我们的图谱工作和核组织研究的信息，我们将准确地确定这些患者中缺失了哪些基因，以及这种缺失是如何导致他们的精神和发育困难的。

We now have an approximate map of the DNA sequence for the entire human genome. However the basic DNA sequence is only a starting block for understanding the complex interplay of factors which regulate the ability of a gene to make the correct protein at the correct time and in the correct cell type. We have a very detailed map of a region of chromosome 16. We want to characterise this region by identifying all the genes and regulatory features within the sequence, and then to look at additional (epigenetic) factors which can influence when and where a gene becomes active. DNA coils down within a cell nucleus with several proteins to form chromatin. We would like to understand how this chromatin is arranged within a nucleus and what changes may be necessary to allow genes to be switched on or off. Within this region of chromosome 16 lie the alpha globin genes. These genes make part of the molecule haemoglobin which carries oxygen in the blood and lack of haemoglobin will give rise to anaemia, which can cause malfunctions in the organs normally supplied with oxygen. When the alpha globin genes are disrupted in some way, patients develop a severe form of anaemia called alpha thalassaemia. Some patients are born with mental retardation and other developmental problems as well as alpha thalassaemia - these patients have a piece of chromosome 16 missing from the region we are studying. With the information from our mapping work and studies of nuclear organisation, we will identify precisely which genes are missing in these patients and how that loss contributes to their mental and developmental difficulties.