Mechanisms of DNA binding and gene regulation by C2H2 zinc finger proteins

基因组编码了非常详细的指令，指示细胞中不同基因需要在何时何地激活。一个被称为“转录因子”的庞大复杂的蛋白质网络执行这些调节指令。转录因子通过与基因组上的特定位点结合来调节基因的活性。这种显著的特异性是由它们识别特定“DNA序列”的能力介导的，这些“DNA序列”是由DNA字母表组成的单词，并标记出应该被每个转录因子结合的基因组位点。“C2H2”锌指家族有700多个成员，构成了最大的一类调节蛋白。我之前的研究表明，C2H2蛋白识别转录因子中最多样化的一组DNA序列，调节大量基因的激活，影响多种细胞通路，是哺乳动物基因组进化的驱动力。然而，这种功能多样性背后的分子机制只得到了部分表征。我们的研究旨在了解C2H2蛋白与DNA结合和基因调控的原理。在这里，我们的目标是研究允许C2H2蛋白识别不同DNA序列的分子机制。我们关注这种多样性的两个方面：(a) C2H2蛋白通过利用蛋白质的不同部分识别多个不同DNA序列的能力，以及(b)它们读取“表观遗传”标记的能力，这是细胞在遗传信息之上覆盖的第二层信息，目的是精确控制基因组的结构和活性。我们将开发新的计算模型，将C2H2蛋白的结构与它们识别的遗传和表观遗传字母表联系起来，揭示这些蛋白质如何在分子水平上读取和解释调控指令。这些模型将帮助我们更好地理解C2H2蛋白调控基因的机制，追溯其进化起源，揭示其新功能。它们还将使我们能够预测以前未表征的C2H2蛋白的分子功能。考虑到这些蛋白质在我们基因组的进化和功能中的核心作用，这些研究将使我们能够破译支配我们生物学的基本原理。

The genome encodes highly detailed instructions indicating when and where different genes need to be active in the cell. A massively complex network of proteins called “transcription factors” executes these regulatory instructions. Transcription factors regulate the activity of genes by binding to very specific sites on the genome. This remarkable specificity is mediated by their ability to recognize particular “DNA sequences”, words that are made of the DNA alphabet and mark the genomic sites that should be bound by each transcription factor.With over 700 members, the “C2H2” zinc finger family constitutes the largest class of regulatory proteins. My previous research has shown that the C2H2 proteins recognize the most diverse set of DNA sequences among transcription factors, regulate the activation of a large number of genes, affect various cellular pathways, and have been a driving force in the evolution of the mammalian genome. However, the molecular mechanisms that underlie this functional diversity have only been partially characterized. Our research aims to understand the principles of DNA binding and gene regulation by C2H2 proteins.Here, we aim to study the molecular mechanisms that allow the C2H2 proteins to recognize diverse DNA sequences. We focus on two aspects of this diversity: (a) the ability of C2H2 proteins to recognize multiple distinct DNA sequences through utilization of different parts of the protein, and (b) their ability to read “epigenetic” marks, a second layer of information that the cell overlays on top of the genetic information in order to precisely control the architecture and the activity of the genome. We will develop novel computational models that connect the structure of C2H2 proteins to the genetic and epigenetic alphabet that they recognize, revealing how regulatory instructions are read and interpreted by these proteins at the molecular level. These models will help us better understand the mechanisms of gene regulation by C2H2 proteins, trace their evolutionary origins, and reveal new functions for them. They will also enable us to predict the molecular functions of previously uncharacterized C2H2 proteins. Given the central role of these proteins in the evolution and function of our genome, these studies will allow us to decipher the fundamental principles that govern our biology.