Wheat supplies about 20% of the total food calories consumed worldwide and is a national staple in many countries. Besides being a key source of plant proteins, it is also a major cause of many dietinduced health issues, especially celiac disease. The only effective treatment for this disease is a total gluten-free diet. The present report describes an effort to develop a natural dietary therapy for this disorder by transcriptional suppression of wheat DEMETER (DME) homeologs using RNA interference. DME encodes a 5-methylcytosine DNA glycosylase responsible for transcriptional derepression of gliadins and low-molecular-weight glutenins (LMWgs) by active demethylation of their promoters in the wheat endosperm. Previous research has demonstrated these proteins to be the major source of immunogenic epitopes. In this research, barley and wheat DME genes were cloned and localized on the syntenous chromosomes. Nucleotide diversity among DME homeologs was studied and used for their virtual transcript profiling. Functional conservation of DME enzyme was confirmed by comparing the motif and domain structure within and across the plant kingdom. Presence and absence of CpG islands in prolamin gene sequences was studied as a hallmark of hypo-and hypermethylation, respectively. Finally the epigenetic influence of DME silencing on accumulation of LMWgs and gliadins was studied using 20 transformants expressing hairpin RNA in their endosperm. These transformants showed up to 85.6% suppression in DME transcript abundance and up to 76.4% reduction in the amount of immunogenic prolamins, demonstrating the possibility of developing wheat varieties compatible for the celiac patients.gluten intolerance | autoimmune reaction | prophylactic measure T he highly homologous seed storage proteins of wheat and barley dubbed as prolamins are classified on the basis of their physiochemical properties into alcohol-soluble gliadins and insoluble glutenins. The gliadins, based on their chemical composition and electrophoretic mobilities, are further classified into sulfur-poor ω-gliadins and the sulfur-rich α/β-and γ-gliadins (1). The corresponding proteins in barley are named as C-, γ-, B-, and D-hordeins (1). The complex mixture of these proteins also known as "gluten", in a single bread wheat variety, is comprised of up to 45 different gliadins, 7-16 low-molecular-weight glutenin (LMWg) subunits and 3-6 high-molecular-weight glutenin (HMWg) subunits (2). These proteins cumulatively represent 80% of proteins stored in wheat endosperm and constitute a major source of plant baseddietary proteins consumed worldwide (3). Despite wheat being the major source of dietary proteins, it is also a key determinant of many diet-induced health issues, especially gluten sensitivity, celiac sprue, schizophrenia, dermatitis herpetiformis, and IgE-mediated allergies including anaphylaxis (3-5). Among these disorders, celiac is one of the most common food-born enteropathies in humans, occurring in various frequencies around the globe (6). In addition to eliciti...