Epigenetics and chromatin dynamics: a review and a paradigm for functional disorders

The digestive tract is arguably the most complex organ system in our body consisting of cells that derive from all three germinal layers and possessing its own nervous and endocrine systems. Digestive diseases are correspondingly diverse in their etiology, pathogenesis and manifestations. Disorders such as gastroparesis, chronic idiopathic intestinal pseudo-obstruction, Hirschsprung’s disease and fecal incontinence originate from the gut’s neuromuscular compartment and involve smooth muscle cells, enteric neurons and mesenchymal cells such as interstitial cells of Cajal (ICC), and are thus termed motility disorders. Another, overlapping group of abnormalities such as functional dyspepsia, irritable bowel syndrome, gastroesophageal reflux and chronic constipation either reflect combinations of altered motility and secretion, visceral hypersensitivity and brain-gut dysregulation, or lack a well-defined pathology, and thus are better classified as functional gastrointestinal disorders.1 Some of these syndromes have estimated prevalence rates reaching 30 percent of the U.S. population and others come with a major social burden or stigma.2 Over the past 150 years, research targeting fundamental mechanisms of gastrointestinal motility provided us with a census of key cell types and defined their role in motility. More recent investigations have uncovered the subcellular and molecular basis of these functions in health and disease3 and begun to analyze the contributions of the intestinal microbiome4 and genetic factors to disease manifestation.3,5–7 However, in the majority of patients no genetic association is obvious, and searching for “organic causes” in the traditional sense may be a futile effort.8 The current working model for the pathogenesis of functional gastrointestinal disorders is the biopsychosocial model,8 which stipulates a key role for a bidirectional interaction between psychosocial factors and physiological mechanisms occurring against a backdrop of genetic predisposition and early life experiences. While the biopsychosocial model has excellent clinical utility, it lacks a biochemically defined integrator that could combine genetic factors and cellular “memories” of past influences with precipitating changes in the external and/or internal environment to determine the individual’s responses at the cellular level and translate them into symptoms and illness behavior. Here we propose that epigenetic control of gene expression is ideally suited for this role, and surveying the associated molecular signatures throughout the genome of affected cells in individual patients would enable researchers to better understand and ultimately control the phenomena described by the biopsychosocial model. In this review we provide a high-level overview of the concepts and basic mechanisms underlying epigenetic control of gene expression, and describe pathways whereby environmental factors can cause heritable alterations in phenotype by modifying the epigenome. Finally, we identify aspects of functional gastrointestinal and motility disorders where epigenetic mechanisms are most likely to play important pathogenetic roles. Additional details and references are provided as Supporting Information.