Protein-based Molecular Memories in Gene Regulation, Disease, and Development

 描述（由申请人提供）：许多全基因组关联研究无法确定我们已知可遗传性状的遗传基础。在某些情况下，这显然是由于遗传复杂性和上位性的异常程度。然而，在其他情况下，原因是难以捉摸的。在他们的一生中，由于不同的环境刺激，个体通常会经历基因表达的短暂变化。传统上认为，这些反应一旦衰退，就没有可遗传的影响。然而，我们最近发现，这样的环境刺激经常诱导蛋白质构象的自我永存的变化。这最常见于调节基因表达的蛋白质：转录因子和RNA结合蛋白。这些蛋白质构象的自模板变化可以被广泛地定义为“朊病毒”，尽管它们的结构通常不匹配原型朊病毒PrP的交叉β折叠淀粉样蛋白。然而，像已知的朊病毒一样，蛋白质功能的相应变化可以从一代遗传到下一代，而基因组没有任何变化2 -4。从这个意义上说，这种基于蛋白质的遗传代表了表观遗传学的极端形式。该项目的目标是系统地识别和表征真核生物蛋白质组中相似的表观遗传元件，并研究它们对疾病，发育和进化的影响。我们的研究结果还将提供一个机制的理解，蛋白质稳态如何燃料遗传是准拉马克的性格，但牢牢扎根于达尔文的突变和自然选择的框架。新的创新基金将使我的实验室能够开展高风险的科学研究，这既有助于揭示生物学这一新领域的原理，也有助于研究我们发现的治疗意义。

 DESCRIPTION (provided by applicant): Many genome-wide association studies have been unable to identify the genetic basis of traits that we know to be heritable. In some cases this is clearly due to an extraordinary degree of genetic complexity and epistasis. Yet in other cases the reasons are elusive. During their lifetimes, individuals commonly experience transient changes in gene expression as a result of different environmental stimuli. These responses are classically thought to have no heritable influence once they decay. However, we have recently discovered that such environmental stimuli frequently induce self-perpetuating changes in protein conformations. This occurs most commonly in proteins that regulate gene expression: transcription factors and RNA binding proteins. These self-templating changes in protein conformation can be broadly defined as `prions,' although their structures do not usually match the cross-beta sheet amyloids of the archetypical prion PrP. However, like known prions, corresponding changes in protein function are heritable from one generation to the next without any change to the genome2-4. In this sense, such protein-based inheritance represents and extreme form of epigenetics. The goals of this project are to systematically identify and characterize similar epigenetic elements in eukaryotic proteomes and investigate their influence on disease, development, and evolution. Our results will also providing a mechanistic understanding of how protein homeostasis fuels inheritance that is quasi-Lamarckian in character, but firmly rooted in a Darwinian framework of mutation and natural selection. New innovator funding will enable my laboratory to carry out the high-risk science necessary both to uncover the principles of this new realm of biology and to investigate the therapeutic implications of our findings.