Global Impairment of Immediate-Early Genes Expression in Rett Syndrome Models and Patients Linked to Myelination Defects
Por:
Petazzi P, Jorge-Torres OC, Gomez A, Scognamiglio I, Serra-Musach J, Merkel A, Grases D, Xiol-Viñas C, O'Callaghan-Gordo M, Armstrong-Moron J, Esteller M and Guil S
Publicada:
1 ene 2023
Ahead of Print:
11 ene 2023
Resumen:
Rett syndrome (RTT) is a severe neurodevelopmental disease caused almost exclusively by mutations to the MeCP2 gene. This disease may be regarded as a synaptopathy, with impairments affecting synaptic plasticity, inhibitory and excitatory transmission and network excitability. The complete understanding of the mechanisms behind how the transcription factor MeCP2 so profoundly affects the mammalian brain are yet to be determined. What is known, is that MeCP2 involvement in activity-dependent expression programs is a critical link between this protein and proper neuronal activity, which allows the correct maturation of connections in the brain. By using RNA-sequencing analysis, we found several immediate-early genes (IEGs, key mediators of activity-dependent responses) directly bound by MeCP2 at the chromatin level and upregulated in the hippocampus and prefrontal cortex of the Mecp2-KO mouse. Quantification of the IEGs response to stimulus both in vivo and in vitro detected an aberrant expression pattern in MeCP2-deficient neurons. Furthermore, altered IEGs levels were found in RTT patient's peripheral blood and brain regions of post-mortem samples, correlating with impaired expression of downstream myelination-related genes. Altogether, these data indicate that proper IEGs expression is crucial for correct synaptic development and that MeCP2 has a key role in the regulation of IEGs.
Filiaciones:
Petazzi P:
Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Carrer Casanova 143, 400° floor, 08036 Barcelona, Spain
RICORS-TERAV, Instituto de Salud Carlos III, 28029 Madrid, Spain
Jorge-Torres OC:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916 Barcelona, Spain
Gomez A:
Biosciences Department, Faculty of Sciences and Technology (FCT), University of Vic-Central University of Catalonia (UVic-UCC), C. de la Laura, 13, 08500 Vic, Spain
Scognamiglio I:
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain
Serra-Musach J:
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain
Merkel A:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916 Barcelona, Spain
Grases D:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916 Barcelona, Spain
Xiol-Viñas C:
Fundación San Juan de Dios, 08950 Barcelona, Spain
Servei de Medicina Genètica i Molecular, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
O'Callaghan-Gordo M:
Clínica Rett, Neurology Department, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain
Armstrong-Moron J:
Servei de Medicina Genètica i Molecular, Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, 08950 Barcelona, Spain
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain
Esteller M:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916 Barcelona, Spain
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), 28029 Madrid, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08907 Barcelona, Spain
Guil S:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08916 Barcelona, Spain
Germans Trias i Pujol Health Science Research Institute, Badalona, 08916 Barcelona, Spain
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