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Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression

Chromatin regulation and alternative splicing are both critical mechanisms guiding gene expression. Studies have demonstrated that histone modifications can influence alternative splicing decisions, but less is known about how alternative splicing may impact chromatin. Here, we demonstrate that seve...

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Autores principales: Agosto, Laura M., Mallory, Michael J., Ferretti, Max B., Blake, Davia, Krick, Keegan S., Gazzara, Matthew R., Garcia, Benjamin A., Lynch, Kristen W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113009/
https://www.ncbi.nlm.nih.gov/pubmed/36933216
http://dx.doi.org/10.1016/j.celrep.2023.112273
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author Agosto, Laura M.
Mallory, Michael J.
Ferretti, Max B.
Blake, Davia
Krick, Keegan S.
Gazzara, Matthew R.
Garcia, Benjamin A.
Lynch, Kristen W.
author_facet Agosto, Laura M.
Mallory, Michael J.
Ferretti, Max B.
Blake, Davia
Krick, Keegan S.
Gazzara, Matthew R.
Garcia, Benjamin A.
Lynch, Kristen W.
author_sort Agosto, Laura M.
collection PubMed
description Chromatin regulation and alternative splicing are both critical mechanisms guiding gene expression. Studies have demonstrated that histone modifications can influence alternative splicing decisions, but less is known about how alternative splicing may impact chromatin. Here, we demonstrate that several genes encoding histone-modifying enzymes are alternatively spliced downstream of T cell signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones, resulting in changes to histone modifications and gene expression. Notably, the long isoform, which is induced by the RNA-binding protein CELF2, promotes expression of several critical T cell surface proteins including CD3, CD28, and CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on histone modification and gene expression that contributes to T cell development.
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spelling pubmed-101130092023-04-18 Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression Agosto, Laura M. Mallory, Michael J. Ferretti, Max B. Blake, Davia Krick, Keegan S. Gazzara, Matthew R. Garcia, Benjamin A. Lynch, Kristen W. Cell Rep Article Chromatin regulation and alternative splicing are both critical mechanisms guiding gene expression. Studies have demonstrated that histone modifications can influence alternative splicing decisions, but less is known about how alternative splicing may impact chromatin. Here, we demonstrate that several genes encoding histone-modifying enzymes are alternatively spliced downstream of T cell signaling pathways, including HDAC7, a gene previously implicated in controlling gene expression and differentiation in T cells. Using CRISPR-Cas9 gene editing and cDNA expression, we show that differential inclusion of HDAC7 exon 9 controls the interaction of HDAC7 with protein chaperones, resulting in changes to histone modifications and gene expression. Notably, the long isoform, which is induced by the RNA-binding protein CELF2, promotes expression of several critical T cell surface proteins including CD3, CD28, and CD69. Thus, we demonstrate that alternative splicing of HDAC7 has a global impact on histone modification and gene expression that contributes to T cell development. 2023-03-28 2023-03-17 /pmc/articles/PMC10113009/ /pubmed/36933216 http://dx.doi.org/10.1016/j.celrep.2023.112273 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ).
spellingShingle Article
Agosto, Laura M.
Mallory, Michael J.
Ferretti, Max B.
Blake, Davia
Krick, Keegan S.
Gazzara, Matthew R.
Garcia, Benjamin A.
Lynch, Kristen W.
Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title_full Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title_fullStr Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title_full_unstemmed Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title_short Alternative splicing of HDAC7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
title_sort alternative splicing of hdac7 regulates its interaction with 14-3-3 proteins to alter histone marks and target gene expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113009/
https://www.ncbi.nlm.nih.gov/pubmed/36933216
http://dx.doi.org/10.1016/j.celrep.2023.112273
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