Decoding the mammalian regulatory genome

解码哺乳动物调控基因组

• 批准号: RGPIN-2020-05972
• 负责人: Mitchell, Jennifer
• 金额: $ 5.03万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746527
• 关键词: Decoding; mammalian; regulatory; genome

Despite completion of the human genome sequence 16 years ago we are currently not able to determine the function of the vast majority of this sequence. We understand how to read the sequence code within gene coding regions but these are 98% of the genome are gene regulatory elements that turn genes on/off in specific cells. These regulatory elements are the instructions for specific cell types. They cause the activation of different groups of genes in brain, blood and heart cells, for example. My research studies an activating type of regulatory element called enhancers. Enhancers are short sequences of about 500 bases that turn on specific genes when their protein product is needed. Although we know that enhancers are important for the proper development of complex organisms and are often the cause of specific differences in the body plan of different species we actually know remarkably little about the sequence code that gives them their function. We are not able to scan the genome sequence to find enhancers or interpret the function of different parts of the sequence when we do know the location of an enhancer. This is like having a book written in a language you can't read. Or, as we have fully sequenced genomes for more than 100 mammals, an entire library of books that you can't read. Recent work by my team has determined new information about the enhancer regulatory code. We used computational biology to predict the conserved functional units in pluripotent stem cell (PSC) enhancers using sequence conservation across 5 mammals. We found there is a larger number of sequence units contributing to enhancer activity than was previously appreciated. More than 10 sites that bind transcription factors are required for robust enhancer activity. We now understand enough of the code for PSCs to make synthetic sequences with function similar to natural enhancers; we can write our own sentences. Over the next 5 years my research team will expand the approach we developed in one cell type to predict the enhancer regulatory code for multiple different cell types. We will address three key questions: 1) Why are so many transcription factor binding sites needed for enhancer activity? 2) How is the regulatory code different in different cell types? 3) What is the best computational approach to fully decode mammalian genomes? In the long term fully decoding genome sequences will allow us to predict how regulatory sequence changes will affect the expression of specific genes. This will have widespread impact on our understanding of development, evolution and the underlying cause of phenotype variation in populations.

尽管人类基因组序列在16年前就完成了，但我们目前还不能确定绝大多数序列的功能。我们知道如何读取基因编码区域内的序列密码，但98%的基因组是基因调控元件，它们在特定细胞中开启或关闭基因。这些调控元件是特定细胞类型的指令。例如，它们会激活大脑、血液和心脏细胞中不同组的基因。我的研究研究了一种叫做增强子的激活型调节元件。增强子是由大约500个碱基组成的短序列，当需要特定基因的蛋白质产物时，它们会启动特定基因。虽然我们知道增强子对复杂生物体的正常发育很重要，而且常常是不同物种身体结构的特定差异的原因，但我们实际上对赋予它们功能的序列代码知之甚少。当我们知道增强子的位置时，我们无法扫描基因组序列以找到增强子或解释序列不同部分的功能。这就像用一种你看不懂的语言写的书。或者，就像我们已经完成了100多种哺乳动物的基因组测序一样，一整个图书馆的书你都看不懂。我的团队最近的工作确定了有关增强剂监管代码的新信息。我们利用计算生物学方法预测了5种哺乳动物多能干细胞（PSC）增强子的保守功能单元。我们发现，与之前认识到的相比，有更多的序列单元对增强子活性有贡献。强增强子活性需要10多个结合转录因子的位点。我们现在对psc的编码有了足够的了解，可以合成与天然增强子功能相似的序列；我们可以自己写句子。在接下来的5年里，我的研究团队将扩展我们在一种细胞类型中开发的方法，以预测多种不同细胞类型的增强子调控代码。我们将解决三个关键问题：1)为什么增强子活性需要如此多的转录因子结合位点？2)不同细胞类型的调控码有何不同？3)完全解码哺乳动物基因组的最佳计算方法是什么？从长远来看，完全解码基因组序列将使我们能够预测调控序列的变化将如何影响特定基因的表达。这将对我们对种群中表型变异的发展、进化和潜在原因的理解产生广泛的影响。