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

基因调控、疾病和发育中基于蛋白质的分子记忆

基本信息

批准号：
8955209
负责人：
Daniel Jarosz
金额：
$ 237万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

项目摘要

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.

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的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。在某些情况下，原因是难以捉摸的，个体在一生中通常会因不同的环境刺激而经历短暂的基因表达变化，这些反应通常被认为一旦衰退就不会产生遗传影响。经常诱发蛋白质构象的自我持续变化。这种情况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我模板变化可以广泛地定义为“朊病毒”，尽管它们的结构通常不匹配。然而，与已知的朊病毒一样，蛋白质功能的变化可以从一代遗传到下一代，而基因组不会发生任何变化2-4。该项目的目标是系统地识别和表征真核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，我们的结果还将提供对蛋白质稳态如何促进的机制理解。新的创新者资助将使我的实验室能够开展必要的高风险科学，以揭示这一新的原理。生物学领域并研究我们的发现的治疗意义。