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Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons

Taking advantage of the fast-growing knowledge of RNA-binding proteins (RBPs) we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons (iNeurons) modelling the neurodevelopmental Rubinstein Taybi Syndrome (RSTS) caused by mutations in the...

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Autores principales: Larizza, Lidia, Calzari, Luciano, Alari, Valentina, Russo, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer - Medknow 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451555/
https://www.ncbi.nlm.nih.gov/pubmed/34100419
http://dx.doi.org/10.4103/1673-5374.314286
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author Larizza, Lidia
Calzari, Luciano
Alari, Valentina
Russo, Silvia
author_facet Larizza, Lidia
Calzari, Luciano
Alari, Valentina
Russo, Silvia
author_sort Larizza, Lidia
collection PubMed
description Taking advantage of the fast-growing knowledge of RNA-binding proteins (RBPs) we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons (iNeurons) modelling the neurodevelopmental Rubinstein Taybi Syndrome (RSTS) caused by mutations in the genes encoding CBP/p300 acetyltransferases. We discuss top and functionally connected downregulated genes sorted to “RNA processing” and “Ribonucleoprotein complex biogenesis” Gene Ontology clusters. The first set of downregulated RBPs includes members of hnRNHP (A1, A2B1, D, G, H2-H1, MAGOHB, PAPBC), core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families, acting in precursor messenger RNA alternative splicing and processing. Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4 (SRRM4) protein, the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons, RSTS iNeurons show downregulated genes for proteins impacting this network. We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS. The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins, such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation. These nucleolar proteins are “dual” players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1, a transcriptional regulator of the circadian rhythm. Additional downregulated genes for “dual specificity” RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS. We underline the hub position of CBP/p300 in chromatin regulation, the impact of its defect on neurons’ post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders.
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spelling pubmed-84515552021-10-18 Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons Larizza, Lidia Calzari, Luciano Alari, Valentina Russo, Silvia Neural Regen Res Review Taking advantage of the fast-growing knowledge of RNA-binding proteins (RBPs) we review the signature of downregulated genes for RBPs in the transcriptome of induced pluripotent stem cell neurons (iNeurons) modelling the neurodevelopmental Rubinstein Taybi Syndrome (RSTS) caused by mutations in the genes encoding CBP/p300 acetyltransferases. We discuss top and functionally connected downregulated genes sorted to “RNA processing” and “Ribonucleoprotein complex biogenesis” Gene Ontology clusters. The first set of downregulated RBPs includes members of hnRNHP (A1, A2B1, D, G, H2-H1, MAGOHB, PAPBC), core subunits of U small nuclear ribonucleoproteins and Serine-Arginine splicing regulators families, acting in precursor messenger RNA alternative splicing and processing. Consistent with literature findings on reduced transcript levels of serine/arginine repetitive matrix 4 (SRRM4) protein, the main regulator of the neural-specific microexons splicing program upon depletion of Ep300 and Crebbp in mouse neurons, RSTS iNeurons show downregulated genes for proteins impacting this network. We link downregulated genes to neurological disorders including the new HNRNPH1-related intellectual disability syndrome with clinical overlap to RSTS. The set of downregulated genes for Ribosome biogenesis includes several components of ribosomal subunits and nucleolar proteins, such NOP58 and fibrillarin that form complexes with snoRNAs with a central role in guiding post-transcriptional modifications needed for rRNA maturation. These nucleolar proteins are “dual” players as fibrillarin is also required for epigenetic regulation of ribosomal genes and conversely NOP58-associated snoRNA levels are under the control of NOP58 interactor BMAL1, a transcriptional regulator of the circadian rhythm. Additional downregulated genes for “dual specificity” RBPs such as RUVBL1 and METTL1 highlight the links between chromatin and the RBP-ome and the contribution of perturbations in their cross-talk to RSTS. We underline the hub position of CBP/p300 in chromatin regulation, the impact of its defect on neurons’ post-transcriptional regulation of gene expression and the potential use of epidrugs in therapeutics of RBP-caused neurodevelopmental disorders. Wolters Kluwer - Medknow 2021-06-07 /pmc/articles/PMC8451555/ /pubmed/34100419 http://dx.doi.org/10.4103/1673-5374.314286 Text en Copyright: © Neural Regeneration Research https://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
spellingShingle Review
Larizza, Lidia
Calzari, Luciano
Alari, Valentina
Russo, Silvia
Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title_full Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title_fullStr Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title_full_unstemmed Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title_short Genes for RNA-binding proteins involved in neural-specific functions and diseases are downregulated in Rubinstein-Taybi iNeurons
title_sort genes for rna-binding proteins involved in neural-specific functions and diseases are downregulated in rubinstein-taybi ineurons
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451555/
https://www.ncbi.nlm.nih.gov/pubmed/34100419
http://dx.doi.org/10.4103/1673-5374.314286
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