Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond

Environmental factors (e.g., malnutrition and physical inactivity) contribute largely to metabolic disorders including obesity, type 2 diabetes, cardiometabolic disease and nonalcoholic fatty liver diseases. The abnormalities in metabolic activity and pathways have been increasingly associated with altered DNA methylation, histone modification and noncoding RNAs, whereas lifestyle interventions targeting diet and physical activity can reverse the epigenetic and metabolic changes. Here we review recent evidence primarily from human studies that links DNA methylation reprogramming to metabolic derangements or improvements, with a focus on cross-tissue (e.g., the liver, skeletal muscle, pancreas, adipose tissue and blood samples) epigenetic markers, mechanistic mediators of the epigenetic reprogramming, and the potential of using epigenetic traits to predict disease risk and intervention response. The challenges in epigenetic studies addressing the mechanisms of metabolic diseases and future directions are also discussed and prospected.     

Epigenetic reprogramming: roads to pluripotency

Epigenetic reprogramming provides valuable resources for customized pluripotent stem cells generation, which are thought to be important bases of future regenerative medicine. Here we review the commonly used methods for epigenetic reprogramming: somatic cell nuclear transfer, cell fusion, cell extract treatment, inducing pluripotency by defined molecules, and briefly discuss their advantages and limitations. Finally we propose that mechanisms underlying epigenetic reprogramming and safety evaluation platform will be future research directions.     

Against all odds: Numerical assessment by tufted capuchin monkeys

When competitors are able to assess the asymmetry in the resource holding potential before interacting, individuals or groups should avoid interacting with stronger opponents, thereby avoiding the energy costs and risk of injury associated with aggressive intergroup encounters. Thus, escalated aggression is expected only between closely matched competitors. Among Argentine tufted capuchin monkeys (Sapajus nigritus), intergroup dominance is decided by the asymmetry in male group size. Using playback experiments, I simulated intergroup encounters with neighboring groups, manipulating both the apparent numerical asymmetry and the resource context. During experimental trials, I recorded the approach behavior of the focal individual, as well as changes in neighbor density and individual travel speed following the presentation of the playback stimulus, to assess whether individual willingness to participate in resource defense was affected by the probability of winning the encounter. In spite of the competitive disadvantage, neither males nor females showed a decreased probability of approach when the numerical odds strongly favored the opposing group. Instead decisions regarding whether to participate appear to be driven primarily by the resource context. Nevertheless, changes in individual behavior during approaches suggest that tufted capuchin monkeys are sensitive to the relative odds. Individuals accelerated less when approaching a larger group, although no changes in neighbor density were apparent. The absence of an effect of the numerical asymmetry on willingness to approach the playback speaker suggests that subordinate groups benefit from engaging in intergroup aggression with larger neighbors, despite the high probability of losing. These encounters may serve to assess the current subjective resource valuation of the neighboring group or limit territorial expansion by large groups by decreasing the marginal value of home range exclusivity. Because these encounters are riskier, however, individuals appear to alter their approaches, becoming more tentative as the numerical odds increasingly favor the opposing group.     

Epigenetic reprogramming: Prdm14 hits the accelerator

Cell Stem Cell 10 4, 425–439 (2012); published online April062012The release of epigenetic boundaries during epigenetic reprogramming is poorly understood. In the recent issue of Cell Stem Cell Journal, Gillich and colleagues identify a unique role for Prdm14 in the acceleration of this process (Gillich et al, 2012).Pluripotent stem cells can be established from pre-implantation blastocyst embryos (embryonic stem cells, ESCs) as well as from the post-implantation epiblast stem cells (EpiSCs; Chenoweth et al, 2010). Murine ESCs and EpiSCs both express central pluripotency factors such as Oct4, Nanog and Sox2, yet the different developmental origins of these two cell types is clearly reflected in their molecular, epigenetic and functional properties. Murine ESCs appear to exist in a unique ‘naive'' state reminiscent of the pre-implantation epiblast. They are characterized by the expression of germ cell–related genes, a remarkably open chromatin structure with two active X chromosomes, and the functional ability to contribute to chimera formation upon blastocyst complementation (Nichols and Smith, 2011). In contrast, EpiSCs reflect the properties of the post-implantation epiblast, characterized by low-level expression of early determinants of somatic differentiation, a near-absence of germ cell gene expression, inactivation of one of the X chromosomes and negligible ability to support the development of chimeric mice. The conversion of primed to naive pluripotent state requires the release of epigenetic restrictions that are established in the post-implantation epiblast. It is thus a reprogramming process akin to the derivation of induced pluripotent stem cells (iPSCs) from somatic cells. The results on Prdm14 from Gillich and colleagues offer new insights into the underlying molecular mechanisms governing epigenetic reprogramming.     

体细胞核移植后表观遗传重编程的异常及其修复

体细胞核移植(Somatic cell nuclear transfer, SCNT)是指将高度分化的体细胞移入到去核的卵母细胞中发育并最终产生后代的技术。然而, 体细胞克隆的总体效率仍然处于一个较低的水平, 主要原因之一是由于体细胞供体核不完全的表观遗传重编程, 包括DNA甲基化、组蛋白乙酰化、基因组印记、X染色体失活和端粒长度等修饰出现的异常。使用一些小分子化合物以及Xist基因的敲除或敲低等方法能修复表观遗传修饰错误, 辅助供体核的重编程, 从而提高体细胞克隆效率, 使其更好地应用于基础研究和生产实践。文章对体细胞核移植后胚胎发育过程中出现的异常表观遗传修饰进行了综述, 并着重论述了近年来有关修复表观遗传错误的研究进展。     

Epigenetic events in mammalian germ-cell development: reprogramming and beyond

The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased- for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself--for example, epigenetics contributes to the gene-expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health.