The regulatory architecture of the Hmx2-Hmx3 gene pair

特化细胞和结构的发育依赖于转录因子基因，其蛋白质产物反过来调节其他基因的表达。转录因子蛋白质与位于基因附近的特定DNA片段（通常称为增强子）相互作用。最近，我们在有颌脊椎动物（哺乳动物、鸟类、鱼类等）中发现了一对独特的保守基因。这些基因属于Hmx家族，它们编码转录因子，并且对大脑、脊髓和头部神经节的某些部分具有特异性，这些部分将感官信息从耳朵传递到大脑。这对基因两侧是两个增强子，它们彼此相似，比迄今为止发现的任何增强子都更加保守。它们在无颌鱼类（如七鳃鳗）中高度保守，七鳃鳗是最早分化的脊椎动物群体，它们甚至在海squares中也很好，海squares是最接近脊椎动物的无脊椎动物，至少在5亿年前从脊椎动物谱系中分离出来。这种保守程度是不寻常的，只能反映极端的“进化限制”，即进化不容忍序列的变化，因为它们的功能是如此重要。我们不知道这是为什么，但假设这是由于它们在神经系统中的高度特异性表达和基本功能。在这个项目中，我们试图回答两个相关的问题来验证这个假设：保守增强子是如何工作来控制这样的特异性基因表达的，为什么这样的特异性表达是重要的？我们可以通过三种实验来实现这一点。一个是弄清楚Hmx基因实际上是做什么的：我们预测它们将在广泛不同的物种中控制类似的靶基因组，这为它们的进化提供了部分约束。第二个是揭示增强子是如何工作的：我们可以通过将它们分开并测试片段的功能来做到这一点。第三是揭示增强子序列保守性的基础：我们可以通过研究它们的进化以及保守功能如何映射到保守序列上来做到这一点。这些将共同解决这个基因对的保守性和功能的“如何”和“为什么”。除了揭示大脑的一个重要部分和相关的感觉系统是如何发展的，从研究这种极端情况中获得的见解可能会揭示一些关于基因调控如何工作和进化的一般未知因素。它还告诉我们，我们身体的一个基本部分，我们的感觉神经系统，是如何发展的，它揭示了我们进化历史中的一系列关键步骤。

The development of specialised cells and structures is dependent on transcription factor genes, whose protein products in turn regulate the expression of other genes. Transcription factor proteins interact with specific bits of DNA, often called enhancers, that lie near genes. Recently we have identified a uniquely conserved pair of genes in jawed vertebrates (mammals, birds, fish etc). These genes are in the Hmx family, which encode transcription factors, and are specific to parts of the brain, spinal cord and head ganglia that relay sensory information from the ears to the brain. This pair of genes is flanked by two enhancers that are similar to each other and more deeply conserved than any enhancers identified to date. They are highly conserved in jawless fish like lampreys, the earliest diverging group of living vertebrates, and they even work well in sea squirts, the closest invertebrate to the vertebrates which split from the vertebrate lineage at least 500 million years ago. This level of conservation is unusual and can only reflect extreme 'evolutionary constraint', that is evolution doesn't tolerate changes to the sequences because their function is so important. We don't know why this is, but hypothesise its due to their highly specific expression and essential function in the nervous system.In this project we seek to answer two related questions that test this hypothesis: how do the conserved enhancers work to control such specific gene expression, and why is such specific expression important? We can do this through three types of experiment. One is to work out what Hmx genes actually do: we predict that they will control similar sets of target genes in widely different species and this provides part of the constraint on their evolution. A second is to uncover how the enhancers work: we can do this by breaking them apart and testing the functions of the pieces. The third is to uncover what underlies the conservation of enhancer sequences: we can do this by studying their evolution and how conserved functions map onto conserved sequences.Together these will address the 'how' and the 'why' of the conservation and function of this gene pair. As well as revealing how an important part of the brain and associated sensory systems develop, insight gained from examining such an extreme case may shed light on some of the general unknowns about how gene regulation works and evolves. It also tells us about how a fundamental part of our own bodies, our sensory nervous system, develops, and it reveals a key set of steps in our evolutionary past.