Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome
Por:
Siqueira E, Obiols-Guardia A, Jorge-Torres OC, Oliveira-Mateos C, Soler M, Ramesh-Kumar D, Setién F, van Rossum D, Pascual-Alonso A, Xiol-Viñas C, Ivan C, Shimizu M, Armstrong-Moron J, Calin GA, Pasterkamp RJ, Esteller M and Guil S
Publicada:
8 mar 2022
Ahead of Print:
1 ene 2022
Resumen:
Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.
Filiaciones:
Siqueira E:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, 08908 Catalonia, Spain
National Council for Scientific and Technological Development (CNPq), Brasilia, 71605-001 Federal District, Brazil
Obiols-Guardia A:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, 08908 Catalonia, Spain
Jorge-Torres OC:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, 08908 Catalonia, Spain
Oliveira-Mateos C:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Soler M:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Ramesh-Kumar D:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Setién F:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
van Rossum D:
Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CG Utrecht, the Netherlands
Pascual-Alonso A:
Fundación San Juan de Dios, Barcelona, 08950 Catalonia, Spain
Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, 08950 Catalonia, Spain
Xiol-Viñas C:
Fundación San Juan de Dios, Barcelona, 08950 Catalonia, Spain
Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, 08950 Catalonia, Spain
Ivan C:
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Shimizu M:
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Armstrong-Moron J:
Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, 08950 Catalonia, Spain
Servei de Medicina Genètica i Molecular, Hospital Sant Joan de Déu, Barcelona, 08950 Catalonia, Spain
CIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III, 28029 Madrid, Spain
Calin GA:
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Pasterkamp RJ:
Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, 3584 CG Utrecht, the Netherlands
Esteller M:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, 08010 Catalonia, Spain
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, 08907 Catalonia, Spain
Guil S:
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Catalonia, Spain
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, 08908 Catalonia, Spain
Germans Trias i Pujol Health Science Research Institute, Badalona, Barcelona, 08916 Catalonia, Spain
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