The role of genetics in the establishment and maintenance of the epigenome

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 review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease.

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Acknowledgments

We thank OIB (FYCIT) for editorial assistance. This work has been financially supported by FIS (FI07/00380 to C·H.); the FIS/FEDER (PI11/01728) and the ISCIII (CP11/00131) (to A.F·F.); the Spanish Ministry of Health (PI061267; PS09/02454 to M.F·F.); the Spanish National Research Council (CSIC; 200820I172 to M.F·F.); the Community of Asturias (FYCIT IB09-106 to M.F·F.). The IUOPA is supported by the Obra Social Cajastur, Spain.

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Huidobro, C., Fernandez, A.F. & Fraga, M.F. The role of genetics in the establishment and maintenance of the epigenome. Cell. Mol. Life Sci. 70, 1543–1573 (2013). https://doi.org/10.1007/s00018-013-1296-2

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Keywords

  • Epigenetics
  • Mutation
  • Disease