Epigenetic control and probabilistic disease programming

项目摘要 教条教导说，一个人的表型（和疾病）的结果，遗传，环境，和他们的 交互.然而，对人类同卵双胞胎和同基因动物模型的大量研究表明， 疾病变异性的很大一部分不能用遗传和环境因素来解释。比如说， 在单卵双胞胎中，遗传占代谢疾病的约50%，环境占<1%， 留下约50%的显著的无法解释的方差（不一致性）。类似的结果也报告了许多其他人类 疾病和复杂的特征。本项目的长期目标是了解 这种无法解释的表型和疾病变异的潜在机制。操作假设是， 表型变异本身是一种数量性状，有概率，细胞内的过程调节， 表观遗传机制，负责不明原因的表型变异的显着部分。的 假设是基于先前对单倍不足Trim 28 +/D9小鼠的研究，其中遗传和环境 相同的同窝出生仔表现为瘦的或肥胖的，具有很少的中间体（即，表观遗传导致的肥胖 多型性）。TRIM 28 mRNA表达水平也可预测人类儿童的肥胖。这一机构的工作 表明表观遗传沉默者是人类概率过程的主要调节者，也可能是 负责调节表型变异。然而，表观遗传机制和基因组位点 导致这种显著的、概率性的和双稳态的疾病潜力的原因是未知的。在这个领域能够 即使开始破译（epi）遗传结构，调节概率过程和变异性，我们需要 首先确定哪种类型的表观遗传沉默者参与了从一个发育过程到另一个发育过程的基因转换， 轨迹到另一个，以及哪些遗传基因座对转换做出反应。我们将通过执行一项 对Trim 28 +/D9小鼠进行基因-基因和基因-环境上位性实验，并对子代进行评分 稳定性，严重性，和频率（即变异性）的代谢性疾病。对于十字架显示 由于疾病变异性的累加效应，我们将在前体和成熟中进行总RNAseq和RNAACS， 脂肪细胞来鉴定与代谢疾病开关和变异相关的基因组位点。与此 知识，我们将能够产生关于基因，途径和生理的具体假设， 这些机制不仅调节代谢疾病，而且控制作为数量性状的表型变异。

PROJECT SUMMARY Dogma teaches that an individual’s phenotype (and disease) results from genetics, the environment, and their interactions. Yet numerous studies of monozygotic human twins and isogenic animal models indicate that significant portions of disease variability cannot be explained by genetic and environmental inputs. For example, genetics accounts for ~50% and environment accounts for <1% of metabolic disease in monozygotic twins, leaving a striking unexplained variance (discordance) of ~50%. Similar results are reported for many other human diseases and complex traits. The long-term goal of this project is to understand the origins and regulatory mechanisms underlying this unexplained phenotypic and disease variation. The operating hypotheses are that phenotypic variation itself is a quantitative trait, and there are probabilistic, intracellular processes regulated by epigenetic mechanisms that are responsible for significant portions of unexplained phenotypic variation. The hypothesis is based on prior work with haploinsufficient Trim28+/D9 mice, where genetically and environmentally identical littermates emerge as either lean or obese, with few intermediates (i.e., an epigenetically driven obesity polyphenism). TRIM28 mRNA expression levels also predict obesity in human children. This body of work suggests that epigenetic silencers are master regulators of probabilistic processes in humans, and may also be responsible for regulating phenotypic variation. However, the epigenetic mechanisms and genomic loci responsible for this remarkable, probabilistic, and bi-stable disease potential are unknown. Before the field can even begin deciphering the (epi)genetic architecture that regulates probabilistic process and variability, we need to first determine which type of epigenetic silencers are involved in the bistable switch from one development trajectory to the other, and which genetic loci respond to the switch. We will meet this objective by performing a focused gene-gene and gene-environment epistasis experiment with Trim28+/D9 mice, and score the offspring for stability, severity, and frequency (i.e. the variability) of bistable metabolic disease. For crosses showing additive effects on disease variability, we will perform total RNAseq and RELACS in precursor and mature adipocytes to identify genomic loci associated with metabolic disease switches and variation. With this knowledge, we will be able to generate specific hypotheses about the genes, pathways, and physiological mechanisms that not only regulate metabolic disease, but control phenotypic variation as a quantitative trait.