TY - JOUR
T1 - Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome
AU - Siqueira, Edilene
AU - Obiols-Guardia, Aida
AU - Jorge-Torres, Olga C.
AU - Oliveira-Mateos, Cristina
AU - Soler, Marta
AU - Ramesh-Kumar, Deepthi
AU - Setién, Fernando
AU - van Rossum, Daniëlle
AU - Pascual-Alonso, Ainhoa
AU - Xiol, Clara
AU - Ivan, Cristina
AU - Shimizu, Masayoshi
AU - Armstrong, Judith
AU - Calin, George A.
AU - Pasterkamp, R. Jeroen
AU - Esteller, Manel
AU - Guil, Sonia
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2022/3/8
Y1 - 2022/3/8
N2 - 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.
AB - 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.
KW - AMPA receptor
KW - GRIA3
KW - MeCP2
KW - Rett syndrome
KW - SIRT2
KW - T-UCR
KW - circRNA
KW - microtubules
KW - noncoding RNA
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U2 - 10.1016/j.omtn.2021.12.030
DO - 10.1016/j.omtn.2021.12.030
M3 - Article
C2 - 35036070
AN - SCOPUS:85122496448
SN - 2162-2531
VL - 27
SP - 621
EP - 644
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
ER -