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The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts

ABSTRACT: 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. We investigated individual functions of CBP and p300 using a silencing strategy, followed by RNA-sequencing, and pathway enrichment analysis. We have selected stress-related pathways for a further in-depth investigation of individual functions of CBP and p300 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236122 | GEO | 2023/07/04

REPOSITORIES: GEO

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Transcription profiling of mouse embryonic fibroblasts C57Bl/6x129/Sv F2 e14.5 embryos vs controls grown in hypoxic or normoxic conditions

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2007-12-15 | E-GEOD-3196 | biostudies-arrayexpress

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2014-09-29 | E-GEOD-54452 | biostudies-arrayexpress

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