BioEssays | Year: 2012
Priming of lineage-specific genes in pluripotent embryonic stem cells facilitates rapid and coordinated activation of transcriptional programmes during differentiation. There is growing evidence that pluripotency factors play key roles in priming tissue-specific genes and in the earliest stages of lineage commitment. As differentiation progresses, pluripotency factors are replaced at some primed genes by related lineage-specific factors that bind to the same sequences and maintain epigenetic priming until the gene is activated. Polycomb and trithorax group proteins bind many genes in pluripotent cells generating bivalent domains that contain both active and repressive histone modifications. The properties of polycomb proteins suggest that they act as gatekeepers, helping to maintain silencing in pluripotent stem cells while establishing a chromatin environment that is permissive for priming by sequence-specific factors. The overall effect of factor-mediated priming is to initiate the input of information required for cell differentiation before the first lineage choices have been made. © 2012 WILEY Periodicals, Inc.
Discovery medicine | Year: 2011
The study of epigenetic mechanisms in the pathogenesis of autoimmune diseases is receiving unprecedented attention from clinicians and researchers in the field. Autoimmune disorders comprise a wide range of genetically complex diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and multiple sclerosis. Together they affect a significant proportion of the population and have a great economic impact on public health systems. Epigenetic mechanisms control gene expression and are influenced by external stimuli, linking environment and gene function. A variety of environmental agents, such as viral infection, hormones, certain drugs, and pollutants, have been found to influence the development of autoimmune diseases. On the other hand, there is considerable evidence of epigenetic changes, particularly DNA methylation alterations, in diseases like systemic lupus erythematosus, rheumatoid arthritis, or multiple sclerosis. However, the gap in our understanding between the specific effects of external agents and the influence on epigenetic profiles has not yet been filled. Here we review a number of studies describing epigenetic alterations in autoimmune diseases and a range of environmental factors that influence the development of autoimmune diseases. We also discuss potential mechanisms linking environment and epigenetics, consider the prospects for future epigenetic studies addressing the relationship between environment and epigenetics, and comment on the use of drugs with an epigenetic-reversing effect in the clinical management of these diseases. © Discovery Medicine
Current topics in microbiology and immunology | Year: 2012
Despite using the same Rag recombinase machinery expressed in both lymphocyte lineages, V(D)J recombination of immunoglobulins only occurs in B cells and T cell receptor recombination is confined to T cells. This vital segregation of recombination targets is governed by the coordinated efforts of several epigenetic mechanisms that control both the general chromatin accessibility of these loci to the Rag recombinase, and the movement and synapsis of distal gene segments in these enormous multigene AgR loci, in a lineage and developmental stage-specific manner. These mechanisms operate both locally at individual gene segments and AgR domains, and globally over large distances in the nucleus. Here we will discuss the roles of several epigenetic components that regulate V(D)J recombination of the immunoglobulin heavy chain locus in B cells, both in the context of the locus itself, and of its 3D nuclear organization, focusing in particular on non-coding RNA transcription. We will also speculate about how several newly described epigenetic mechanisms might impact on AgR regulation.
Clinical Reviews in Allergy and Immunology | Year: 2010
The existence of phenotypic differences between monozygotic (MZ) twins is a prime case where the relationship between genetic determinants and environmental factors is illustrated. Although virtually identical from a genetic point of view, MZ twins show a variable degree of discordance with respect to different features including susceptibility to disease. Discordance has frequently been interpreted in terms of the impact of the environment with genetics. In this sense, accumulated evidence supports the notion that environmental factors can have a long-term effect on epigenetic profiles and influence the susceptibility to disease. In relation with autoimmune diseases, the identification of DNA methylation changes in individuals who develop the disease, and the influence of inhibitors of DNA methyltransferases and histone modification enzymes in the development of autoimmunity are attracting the attention of researchers in the epigenetics field. In this context, the study of discordant MZ twins constitutes an attractive model to further investigate the epigenetic mechanisms involved in their development as well as to dissect the contribution of environmental traits. The implications of novel strategies to map epigenetic profiles and how the use of MZ twins can contribute to dissect the epigenetic component of autoimmune disease are discussed. © 2009 Humana Press Inc.
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011
Epigenetic reprogramming in the germline provides a developmental model to study the erasure of epigenetic memory as it occurs naturally in vivo in the course of normal embryonic development. Our data show that germline reprogramming comprises both active DNA demethylation and extensive chromatin remodelling that are mechanistically linked through the activation of the base excision DNA repair pathway involved in the DNA demethylation process. The observed molecular hallmarks of the germline reprogramming exhibit intriguing similarities to other dedifferentiation or regeneration systems, pointing towards the existence of unifying molecular pathways underlying cell fate reversal. Elucidation of molecular processes involved in the resetting of epigenetic informationin vivo will thus add to our ability to manipulate cell fate and to restore pluripotency in in vitro settings. © 2011 The Royal Society.