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（由适用提供）：许多全基因组关联研究都无法确定我们知道可以遗传的特征的遗传基础。在某些情况下，这显然是由于遗传复杂性和上毒程度非常高。然而，在其他情况下，原因是弹性。在其一生中，由于不同的环境刺激，个人通常会经历基因表达的短暂变化。这些反应在经典上被认为一旦腐烂就不会产生遗传的影响。但是，我们最近发现，这种环境刺激经常引起蛋白质构象的自我延续变化。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。这些蛋白质构象中的自我示意变化可以广泛地定义为“ prions”，尽管它们的结构通常与原型Prion PRP的跨β板淀粉样蛋白不匹配。但是，像已知的王子一样，蛋白质功能的相应变化是从一代到下一代的遗传性变化，而没有对基因组2-4的任何变化。从这个意义上讲，这种基于蛋白质的遗传代表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蛋白中类似的表观遗传因素，并研究其对疾病，发育和进化的影响。我们的结果还将提供对蛋白质稳态的机械理解，其特征上是准湖泊的遗传，但首先植根于达尔文的突变和自然选择框架。新的Innovator资金将使我的实验室能够开展所必需的高风险科学，以揭示这一新生物学领域的原则，并调查我们发现的治疗意义。