The role of genetics in the establishment and maintenance of the epigenome
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Cellular and Molecular Life Sciences
MULTI-AUTHOR REVIEW
The role of genetics in the establishment and maintenance of the epigenome Covadonga Huidobro · Agustin F. Fernandez · Mario F. Fraga
Received: 29 January 2013 / Revised: 5 February 2013 / Accepted: 5 February 2013 / Published online: 10 March 2013 © Springer Basel 2013
Abstract Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein–Taybi syndrome, Coffin–Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we C. Huidobro · A. F. Fernandez · M. F. Fraga (*) Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA-HUCA), University of Oviedo, Oviedo, Spain e-mail: [email protected] M. F. Fraga Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain
review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease. Keywords Epigenetics · Mutation · Disease
Introduction After the elucidation of the genetic code in the late 1950s, it was considered that the information encoded by genetic material (DNA and mRNA nucleotide sequences) would be unchangeable and pass faithfully from one cell to another and from one generation to the next, except for the occurrence of genetic mutations. However, a few decades ago, a new code arose, namely the epigenetic code, which revealed that the message the nucleotide sequence of DNA harbors could be different depending on the epigenetic marks it contained. Thus, epigenetic marks can be defined as modifications affecting the DNA sequence or associated proteins, like histones, others than the DNA sequence, that are heritable through cell division. DNA methylation, histone modifications, non-coding
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