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Metabolic Deregulations Affecting Chromatin Architecture: One-Carbon Metabolism and Krebs Cycle Impact Histone Methylation.

Abstract : The methylation status of a particular amino acid results from the interplay of two enzymes: “Writers” (methyltransferases) and “Erasers” (demethylases). Methylation of histones in chromatin can be recognized by “Readers” which induce changes in chromatin organization and gene expression, directed by the methylation status. Importantly, the reactions of methylation and demethylation involve several metabolites. Some, such as folate and S-adenosyl-l-methionine, act as cofactors for methyltransferases while flavin adenine dinucleotide and α-ketoglutarate act as cofactors for demethylases. Other metabolites, such as succinate and fumarate, function as enzyme inhibitors. Factors that modulate the levels of these metabolites in the cell therefore affect the dynamics of protein methylation. These factors can include diet, as well as altered expression of enzymes involved in cofactor synthesis through mutations and/or post-translational modifications. For example, methionine is a substrate for S-adenosyl-l-methionine formation, and reduction in its abundance ultimately induces a global reduction in histone methylation in vitro, affecting gene expression. Changes in the metabolic states of cells in diseases such as cancer, and regulation of metabolites required for histone methylation and demethylation, have thus been highlighted as avenues for therapeutic development. In this review, we evaluate the current knowledge concerning methylation of histones, and also of other protein substrates. We document how this is linked to metabolites such as S-adenosyl-l-methionine and other intermediates in the Krebs cycle. Finally, we discuss the implications of deregulation at this level in cancer.
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https://hal.archives-ouvertes.fr/hal-02371144
Contributor : Geneviève Almouzni Connect in order to contact the contributor
Submitted on : Friday, December 11, 2020 - 12:06:28 PM
Last modification on : Tuesday, October 19, 2021 - 11:00:29 AM
Long-term archiving on: : Friday, March 12, 2021 - 6:23:55 PM

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Francisco Saavedra, Ekaterina Boyarchuk, Francisca Alvarez, Geneviève Almouzni, Alejandra Loyola. Metabolic Deregulations Affecting Chromatin Architecture: One-Carbon Metabolism and Krebs Cycle Impact Histone Methylation.. The DNA,RNA, and Histone Methylomes. RNA Technologies., pp.573-606, 2019, 978-3-030-14791-4. ⟨10.1007/978-3-030-14792-1_23⟩. ⟨hal-02371144⟩

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