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, Setien, F, van Rossum, D, Pascual-Alonso, A, Xiol, C, Ivan, C, Shimizu, M, Armstrong, J, Calin, GA, Pasterkamp, RJ, Esteller, M and Guil, S
Publicada:
8 mar 2022
Ahead of Print:
22 dic 2021
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:
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Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain
Natl Council Sci & Technol Dev, CNPq, BR-71605001 Brasilia, DF, Brazil
Obiols-Guardia, A:
Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain
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Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain
Oliveira-Mateos, C:
Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
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Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
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Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
van Rossum, D:
Univ Utrecht, Univ Med Ctr Utrecht Brain Ctr, Dept Translat Neurosci, NL-3584 CG Utrecht, Netherlands
Pascual-Alonso, A:
Fdn San Juan de Dios, Barcelona 08950, Catalonia, Spain
Hosp St Joan de Deu, Inst Recerca Pediat, Barcelona 08950, Catalonia, Spain
Xiol, C:
Fdn San Juan de Dios, Barcelona 08950, Catalonia, Spain
Hosp St Joan de Deu, Inst Recerca Pediat, Barcelona 08950, Catalonia, Spain
Ivan, C:
Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA
Shimizu, M:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA
Armstrong, J:
Hosp St Joan de Deu, Inst Recerca Pediat, Barcelona 08950, Catalonia, Spain
Hosp St Joan de Deu, Serv Med Genet & Mol, Barcelona 08950, Catalonia, Spain
Inst Salud Carlos III, CIBER ER Biomed Network Res Ctr Rare Dis, Madrid 28029, Spain
Calin, GA:
Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 USA
Pasterkamp, RJ:
Univ Utrecht, Univ Med Ctr Utrecht Brain Ctr, Dept Translat Neurosci, NL-3584 CG Utrecht, Netherlands
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Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona 08010, Catalonia, Spain
Univ Barcelona UB, Sch Med & Hlth Sci, Physiol Sci Dept, Barcelona 08907, Catalonia, Spain
:
Josep Carreras Leukaemia Res Inst IJC, Barcelona 08916, Catalonia, Spain
Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Catalonia, Spain
Germans Trias & Pujol Hlth Sci Res Inst, Barcelona 08916, Catalonia, Spain
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