Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Neurogastroenterol Motil. 2012 Dec;24(12):1054-68. doi: 10.1111/nmo.12031. Epub 2012 Oct 24.
Motility and functional gastrointestinal disorders have high prevalence in the community, cause significant morbidity, and represent a major health care burden. Despite major advances in our understanding of the cellular and molecular basis of gastrointestinal neuromuscular functions, many of these diseases still defy mechanistic explanations. The biopsychosocial model underlying the current classification of functional gastrointestinal disorders recognizes and integrates the pathogenetic role of genetic, environmental, and psychosocial factors but has not been associated with specific molecular mechanisms.
Here, we propose that this integrative function is encoded in the chromatin, composed of the DNA and associated histone and non-histone proteins and non-coding RNA. By establishing epigenetically heritable 'molecular memories' of past stimuli including environmental challenges, the chromatin determines an individual's responses to future insults and translates them into high-order outputs such as symptoms and illness behavior. Thus, surveying epigenetic signatures throughout the genome of affected cells in individual patients may make it possible to better understand and ultimately control the phenomena described by the biopsychosocial model. In this review, we provide a high-level but comprehensive description of the concepts and mechanisms underlying epigenetics and chromatin dynamics, describe the mechanisms whereby the environment can alter the epigenome and identify aspects of functional gastrointestinal and motility disorders where epigenetic mechanisms are most likely to play important roles.
运动障碍和功能性胃肠疾病在社区中发病率很高，会导致严重的发病率，并构成主要的医疗保健负担。尽管我们对胃肠道神经肌肉功能的细胞和分子基础有了重大的理解进展，但许多这些疾病仍然无法用机械论来解释。目前功能性胃肠疾病分类所依据的生物心理社会模型认识到并整合了遗传、环境和心理社会因素的发病作用，但与特定的分子机制无关。
在这里，我们提出这种整合功能是由染色质编码的，染色质由 DNA 及其相关的组蛋白和非组蛋白以及非编码 RNA 组成。通过建立对过去刺激（包括环境挑战）的可遗传的“分子记忆”，染色质决定了个体对未来伤害的反应，并将其转化为高级输出，如症状和疾病行为。因此，对个体患者受影响细胞的整个基因组中的表观遗传特征进行调查，可能有助于更好地理解并最终控制生物心理社会模型所描述的现象。在这篇综述中，我们提供了一个关于表观遗传学和染色质动力学的概念和机制的高层次但全面的描述，描述了环境如何改变表观基因组的机制，并确定了在功能性胃肠和运动障碍中，表观遗传机制最有可能发挥重要作用的方面。
