Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome
Siqueira, Edilene; Obiols-Guardia, Aida; Jorge-Torres, Olga C.; Oliveira-Mateos, Cristina; Soler, Marta; Ramesh-Kumar, Deepthi; Setién, Fernando; van Rossum, Daniëlle; Pascual-Alonso, Ainhoa; Xiol, Clara; Ivan, Cristina; Shimizu, Masayoshi; Armstrong, Judith; Calin, George A.; Pasterkamp, R. Jeroen; Esteller, Manel; Guil, Sonia
(2022) Molecular Therapy - Nucleic Acids, volume 27, pp. 621 - 644
(Article)
Abstract
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
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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.
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Keywords: AMPA receptor, circRNA, GRIA3, MeCP2, microtubules, noncoding RNA, Rett syndrome, SIRT2, T-UCR, Drug Discovery, Molecular Medicine, Journal Article
ISSN: 2162-2531
Publisher: Nature Publishing Group
Note: Funding Information: Postmortem brain tissue from control individuals and individuals with RTT was obtained from the National Institutes of Health (NIH) NeuroBioBank at the University of Maryland (Baltimore, MD, USA) and the Human Brain and Spinal Fluid Resource Center, VA West Los Angeles Healthcare Care Center (Los Angeles, CA, USA), which is sponsored by the National Institute of Neurological Disorders (NMSS), and Stroke (NINDS)/National Institute of Mental Health (NIMH), the National Multiple Sclerosis Society, and the Department of Veterans Affairs. Funding Information: We thank the CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation for institutional support, Dr. Vaquero (IJC, Badalona, Spain) for the generous gift of the SIRT2-HA plasmid, and members of the Pasterkamp lab for discussions and help. This work was supported by the Ministerio de Economía y Competitividad and the Instituto de Salud Carlos III , co-financed by the European Development Regional Fund , “A way to achieve Europe” ERDF, under grants PI15/01159 and PI20/00389 (to J.A.), the crowd-funding program PRECIPITA , FondoBiorett and Mi Princesa Rett (to J.A.), the Health and Science Departments of the Catalan Government (Generalitat de Catalunya), the Catalan and Spanish Associations for Rett Syndrome (FinRett, to S.G.), the Epilepsiefonds ( WAR18-05 , to R.J.P.), and the European Union Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie grant agreement 721890 (cirRTrain ITN, to R.J.P.). We are indebted to the “Biobanc de l’Hospital Infantil Sant Joan de Déu per a la Investigació,” integrated in the Spanish Biobank Network of ISCIII, for sample and data procurement. G.A.C. is the Felix L. Haas Endowed Professor in Basic Science. G.A.C.’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC); NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1; NIGMS 1R01GM122775-01; a Team DOD grant (CA160445P1); a Chronic Lymphocytic Leukemia Moonshot Flagship project; a CLL Global Research Foundation 2019 grant; a CLL Global Research Foundation 2020 grant; donor support through Dr. Jaffer Ajani; and the Estate of C.G. Johnson, Jr. A.O.-G. is a pre-doctoral fellow funded by MINECO (BES-2015-071452) and the recipient of an EMBO short-term fellowship (8129). E.S. is a pre-doctoral fellow funded by a “Science without borders” scholarship (202074/2015-3) from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brasilia, Brazil). M.E. is an ICREA Research Professor. Funding Information: We thank the CERCA program (Generalitat de Catalunya) and the Josep Carreras Foundation for institutional support, Dr. Vaquero (IJC, Badalona, Spain) for the generous gift of the SIRT2-HA plasmid, and members of the Pasterkamp lab for discussions and help. This work was supported by the Ministerio de Econom?a y Competitividad and the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund, ?A way to achieve Europe? ERDF, under grants PI15/01159 and PI20/00389 (to J.A.), the crowd-funding program PRECIPITA, FondoBiorett and Mi Princesa Rett (to J.A.), the Health and Science Departments of the Catalan Government (Generalitat de Catalunya), the Catalan and Spanish Associations for Rett Syndrome (FinRett, to S.G.), the Epilepsiefonds (WAR18-05, to R.J.P.), and the European Union Horizon 2020 Research and Innovation Program under Marie Sk?odowska-Curie grant agreement 721890 (cirRTrain ITN, to R.J.P.). We are indebted to the ?Biobanc de l'Hospital Infantil Sant Joan de D?u per a la Investigaci?,? integrated in the Spanish Biobank Network of ISCIII, for sample and data procurement. G.A.C. is the Felix L. Haas Endowed Professor in Basic Science. G.A.C.?s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC); NCI grants 1R01 CA182905-01 and 1R01CA222007-01A1; NIGMS 1R01GM122775-01; a Team DOD grant (CA160445P1); a Chronic Lymphocytic Leukemia Moonshot Flagship project; a CLL Global Research Foundation 2019 grant; a CLL Global Research Foundation 2020 grant; donor support through Dr. Jaffer Ajani; and the Estate of C.G. Johnson, Jr. A.O.-G. is a pre-doctoral fellow funded by MINECO (BES-2015-071452) and the recipient of an EMBO short-term fellowship (8129). E.S. is a pre-doctoral fellow funded by a ?Science without borders? scholarship (202074/2015-3) from Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq, Brasilia, Brazil). M.E. is an ICREA Research Professor. All experiments were conceived by E.S. A.O.-G. O.C.J.-T. and S.G. and carried out mainly by E.S. and A.O.-G. O.C.J.-T. carried out the proteomics analysis and experiments with the N2a model. M.S. performed the methylation analysis and provided technical support. F.S. carried out plasmid construction. C.O.-M. and D.R.-K. performed circRNA characterization. A.P.-A. C.X. and J.A. genotyped the RTT samples. G.A.C. M.S. and C.I. performed T-UCR microarray hybridization and analysis. D.v.R. and R.J.P. provided training and assisted with RNA ISH experiments. S.G. wrote the manuscript with input from all authors. S.G. and M.E. supervised the project. The authors declare no competing interests. Publisher Copyright: © 2021 The Author(s)
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