Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.

Autor:	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 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 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.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2021 Dec 22; Vol. 27, pp. 621-644. Date of Electronic Publication: 2021 Dec 22 (Print Publication: 2022).
DOI:	10.1016/j.omtn.2021.12.030
Abstrakt:	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. Competing Interests: The authors declare no competing interests. (© 2021 The Author(s).)
Databáze:	MEDLINE
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