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Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease

RNA-binding proteins (RBPs) are key players regulating RNA processing and are associated with disorders ranging from cancer to neurodegeneration. Here, we present a proteomics workflow for large-scale identification of RBPs and their RNA-binding regions in the mammalian brain identifying 526 RBPs. A...

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Autores principales: Mullari, Meeli, Fossat, Nicolas, Skotte, Niels H., Asenjo-Martinez, Andrea, Humphreys, David T., Bukh, Jens, Kirkeby, Agnete, Scheel, Troels K. H., Nielsen, Michael L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356804/
https://www.ncbi.nlm.nih.gov/pubmed/37468457
http://dx.doi.org/10.1038/s41467-023-39936-x
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author Mullari, Meeli
Fossat, Nicolas
Skotte, Niels H.
Asenjo-Martinez, Andrea
Humphreys, David T.
Bukh, Jens
Kirkeby, Agnete
Scheel, Troels K. H.
Nielsen, Michael L.
author_facet Mullari, Meeli
Fossat, Nicolas
Skotte, Niels H.
Asenjo-Martinez, Andrea
Humphreys, David T.
Bukh, Jens
Kirkeby, Agnete
Scheel, Troels K. H.
Nielsen, Michael L.
author_sort Mullari, Meeli
collection PubMed
description RNA-binding proteins (RBPs) are key players regulating RNA processing and are associated with disorders ranging from cancer to neurodegeneration. Here, we present a proteomics workflow for large-scale identification of RBPs and their RNA-binding regions in the mammalian brain identifying 526 RBPs. Analysing brain tissue from males of the Huntington’s disease (HD) R6/2 mouse model uncovered differential RNA-binding of the alternative splicing regulator RBM5. Combining several omics workflows, we show that RBM5 binds differentially to transcripts enriched in pathways of neurodegeneration in R6/2 brain tissue. We further find these transcripts to undergo changes in splicing and demonstrate that RBM5 directly regulates these changes in human neurons derived from embryonic stem cells. Finally, we reveal that RBM5 interacts differently with several known huntingtin interactors and components of huntingtin aggregates. Collectively, we demonstrate the applicability of our method for capturing RNA interactor dynamics in the contexts of tissue and disease.
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spelling pubmed-103568042023-07-21 Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease Mullari, Meeli Fossat, Nicolas Skotte, Niels H. Asenjo-Martinez, Andrea Humphreys, David T. Bukh, Jens Kirkeby, Agnete Scheel, Troels K. H. Nielsen, Michael L. Nat Commun Article RNA-binding proteins (RBPs) are key players regulating RNA processing and are associated with disorders ranging from cancer to neurodegeneration. Here, we present a proteomics workflow for large-scale identification of RBPs and their RNA-binding regions in the mammalian brain identifying 526 RBPs. Analysing brain tissue from males of the Huntington’s disease (HD) R6/2 mouse model uncovered differential RNA-binding of the alternative splicing regulator RBM5. Combining several omics workflows, we show that RBM5 binds differentially to transcripts enriched in pathways of neurodegeneration in R6/2 brain tissue. We further find these transcripts to undergo changes in splicing and demonstrate that RBM5 directly regulates these changes in human neurons derived from embryonic stem cells. Finally, we reveal that RBM5 interacts differently with several known huntingtin interactors and components of huntingtin aggregates. Collectively, we demonstrate the applicability of our method for capturing RNA interactor dynamics in the contexts of tissue and disease. Nature Publishing Group UK 2023-07-19 /pmc/articles/PMC10356804/ /pubmed/37468457 http://dx.doi.org/10.1038/s41467-023-39936-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Mullari, Meeli
Fossat, Nicolas
Skotte, Niels H.
Asenjo-Martinez, Andrea
Humphreys, David T.
Bukh, Jens
Kirkeby, Agnete
Scheel, Troels K. H.
Nielsen, Michael L.
Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title_full Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title_fullStr Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title_full_unstemmed Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title_short Characterising the RNA-binding protein atlas of the mammalian brain uncovers RBM5 misregulation in mouse models of Huntington’s disease
title_sort characterising the rna-binding protein atlas of the mammalian brain uncovers rbm5 misregulation in mouse models of huntington’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10356804/
https://www.ncbi.nlm.nih.gov/pubmed/37468457
http://dx.doi.org/10.1038/s41467-023-39936-x
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