Déréglementations métaboliques affectant l'architecture de la chromatine : Métabolisme à un carbone et impact du cycle de Krebs sur la méthylation des histones.

International audienceThe 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.Le statut de méthylation d'un acide aminé particulier résulte de l'interaction de deux enzymes : "Writers" (méthyltransférases) et "Erasers" (déméthylases). La méthylation des histones dans la chromatine peut être reconnue par les "Readers" qui induisent des changements dans l'organisation de la chromatine et l'expression des gènes, dirigés par le statut de méthylation. Il est important de noter que les réactions de méthylation et de déméthylation impliquent plusieurs métabolites. Certains, tels que le folate et la S-adénosyl-l-méthionine, agissent comme cofacteurs des méthyltransférases, tandis que la flavine-adénine-dinucléotide et le α-ketoglutarate agissent comme cofacteurs des déméthylases. D'autres métabolites, tels que le succinate et le fumarate, fonctionnent comme des inhibiteurs d'enzymes. Les facteurs qui modulent les niveaux de ces métabolites dans la cellule affectent donc la dynamique de la méthylation des protéines. Ces facteurs peuvent inclure le régime alimentaire, ainsi que l'altération de l'expression des enzymes impliquées dans la synthèse des cofacteurs par des mutations et/ou des modifications post-traductionnelles. Par exemple, la méthionine est un substrat pour la formation de S-adénosyl-l-méthionine, et la réduction de son abondance induit finalement une réduction globale de la méthylation des histones in vitro, affectant l'expression des gènes. Les modifications de l'état métabolique des cellules dans des maladies telles que le cancer, et la régulation des métabolites nécessaires à la méthylation et à la déméthylation des histones, ont donc été mises en évidence comme des pistes pour le développement thérapeutique. Dans cette revue, nous évaluons les connaissances actuelles concernant la méthylation des histones, ainsi que d'autres substrats protéiques. Nous documentons la façon dont celle-ci est liée à des métabolites tels que la S-adénosyl-l-méthionine et d'autres intermédiaires du cycle de Krebs. Enfin, nous discutons des implications de la déréglementation à ce niveau dans le domaine du cancer

Understanding Factors Associated With Psychomotor Subtypes of Delirium in Older Inpatients With Dementia

Objectives: Few studies have analyzed factors associated with delirium subtypes. In this study, we investigate factors associated with subtypes of delirium only in patients with dementia to provide insights on the possible prevention and treatments. Design: This is a cross-sectional study nested in the “Delirium Day” study, a nationwide Italian point-prevalence study. Setting and Participants: Older patients admitted to 205 acute and 92 rehabilitation hospital wards. Measures: Delirium was evaluated with the 4-AT and the motor subtypes with the Delirium Motor Subtype Scale. Dementia was defined by the presence of a documented diagnosis in the medical records and/or prescription of acetylcholinesterase inhibitors or memantine prior to admission. Results: Of the 1057 patients with dementia, 35% had delirium, with 25.6% hyperactive, 33.1% hypoactive, 34.5% mixed, and 6.7% nonmotor subtype. There were higher odds of having venous catheters in the hypoactive (OR 1.82, 95% CI 1.18-2.81) and mixed type of delirium (OR 2.23, CI 1.43-3.46), whereas higher odds of urinary catheters in the hypoactive (OR 2.91, CI 1.92-4.39), hyperactive (OR 1.99, CI 1.23-3.21), and mixed types of delirium (OR 2.05, CI 1.36-3.07). We found higher odds of antipsychotics both in the hyperactive (OR 2.87, CI 1.81-4.54) and mixed subtype (OR 1.84, CI 1.24-2.75), whereas higher odds of antibiotics was present only in the mixed subtype (OR 1.91, CI 1.26-2.87). Conclusions and Implications: In patients with dementia, the mixed delirium subtype is the most prevalent followed by the hypoactive, hyperactive, and nonmotor subtype. Motor subtypes of delirium may be triggered by clinical factors, including the use of venous and urinary catheters, and the use of antipsychotics. Future studies are necessary to provide further insights on the possible pathophysiology of delirium in patients with dementia and to address the optimization of the management of potential risk factors