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The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels

The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. Furthermore, they serve as co-factors for...

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Autores principales: Krošel, Monika, Gabathuler, Marcel, Moser, Larissa, Maciukiewicz, Malgorzata, Züllig, Thomas, Seifritz, Tanja, Tomšič, Matija, Distler, Oliver, Ospelt, Caroline, Klein, Kerstin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564874/
https://www.ncbi.nlm.nih.gov/pubmed/37816914
http://dx.doi.org/10.1038/s41598-023-44412-z
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author Krošel, Monika
Gabathuler, Marcel
Moser, Larissa
Maciukiewicz, Malgorzata
Züllig, Thomas
Seifritz, Tanja
Tomšič, Matija
Distler, Oliver
Ospelt, Caroline
Klein, Kerstin
author_facet Krošel, Monika
Gabathuler, Marcel
Moser, Larissa
Maciukiewicz, Malgorzata
Züllig, Thomas
Seifritz, Tanja
Tomšič, Matija
Distler, Oliver
Ospelt, Caroline
Klein, Kerstin
author_sort Krošel, Monika
collection PubMed
description The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. Furthermore, they serve as co-factors for transcription factors and acetylate many non-histone proteins. Here we showed that p300 but not CBP protein expression was down regulated by TNF and 4-hydroxynonenal, two factors that mimic inflammation and oxidative stress in the synovial microenvironment. We used existing RNA-sequencing data sets as a basis for a further in-depth investigation of individual functions of CBP and p300 in regulating different stress response pathways in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300.
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spelling pubmed-105648742023-10-12 The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels Krošel, Monika Gabathuler, Marcel Moser, Larissa Maciukiewicz, Malgorzata Züllig, Thomas Seifritz, Tanja Tomšič, Matija Distler, Oliver Ospelt, Caroline Klein, Kerstin Sci Rep Article The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. Furthermore, they serve as co-factors for transcription factors and acetylate many non-histone proteins. Here we showed that p300 but not CBP protein expression was down regulated by TNF and 4-hydroxynonenal, two factors that mimic inflammation and oxidative stress in the synovial microenvironment. We used existing RNA-sequencing data sets as a basis for a further in-depth investigation of individual functions of CBP and p300 in regulating different stress response pathways in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300. Nature Publishing Group UK 2023-10-10 /pmc/articles/PMC10564874/ /pubmed/37816914 http://dx.doi.org/10.1038/s41598-023-44412-z 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
Krošel, Monika
Gabathuler, Marcel
Moser, Larissa
Maciukiewicz, Malgorzata
Züllig, Thomas
Seifritz, Tanja
Tomšič, Matija
Distler, Oliver
Ospelt, Caroline
Klein, Kerstin
The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title_full The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title_fullStr The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title_full_unstemmed The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title_short The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
title_sort histone acetyl transferases cbp and p300 regulate stress response pathways in synovial fibroblasts at transcriptional and functional levels
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10564874/
https://www.ncbi.nlm.nih.gov/pubmed/37816914
http://dx.doi.org/10.1038/s41598-023-44412-z
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