Epigenetic control and probabilistic disease programming

项目总结 Dogma告诉我们，一个人的表型(和疾病)是由遗传、环境和他们的 互动。然而，大量对同卵双胞胎和同基因动物模型的研究表明， 疾病变异性的很大一部分不能用遗传和环境输入来解释。例如, 在同卵双胞胎代谢性疾病中，遗传因素占50%，环境因素占1%。 留下了约50%的惊人的无法解释的差异(不一致)。在许多其他人类身上也报道了类似的结果 疾病和复杂的特征。该项目的长期目标是了解其起源和监管 这种无法解释的表型和疾病变异背后的机制。可操作的假设是 表型变异本身是一个数量性状，存在着由 表观遗传机制是解释不了的表型变异的主要原因。这个 假说是基于之前对单倍体缺陷Trim28+/D9小鼠的研究，在这些小鼠中，遗传和环境因素 相同的产仔后代要么瘦弱，要么肥胖，中间几乎没有中间产物(即表观遗传驱动的肥胖 多面性)。TRIM28mRNA的表达水平也可以预测人类儿童的肥胖。这部作品的主体 提示表观遗传沉默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座位 造成这一显著的、概率的和双稳态疾病的潜在原因尚不清楚。在田野可以 即使开始破译调控概率过程和可变性的(EPI)遗传结构，我们也需要 为了首先确定哪种类型的表观遗传消音器参与了来自一种发展的双稳态开关 轨迹到另一个，以及哪些遗传位点对这种转换做出反应。我们将通过执行一项 对Trim28+/D9小鼠进行聚焦基因-基因和基因-环境上位性实验，并对后代进行评分 关于双稳态代谢性疾病的稳定性、严重性和频率(即变异性)。对于显示的十字架 疾病变异性的加性效应，我们将在先驱体和成熟期进行总RNAseq和RELACS 脂肪细胞识别与代谢性疾病开关和变异相关的基因组基因座。有了这个 知识，我们将能够产生关于基因、途径和生理的具体假说 不仅调控代谢性疾病，而且将表型变异作为数量性状加以控制的机制。

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.