scholarly journals NF‐κB p65 dimerization and DNA‐binding is important for inflammatory gene expression

2018 ◽  
Vol 33 (3) ◽  
pp. 4188-4202 ◽  
Author(s):  
Tabea Riedlinger ◽  
Robert Liefke ◽  
Johanna Meier-Soelch ◽  
Liane Jurida ◽  
Andrea Nist ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

scholarly journals Identification of multiple MAPK-mediated transcription factors regulated by tobacco smoke in airway epithelial cells

2007 ◽  
Vol 293 (2) ◽  
pp. L480-L490 ◽  
Author(s):  
Jinming Zhao ◽  
Richart Harper ◽  
Aaron Barchowsky ◽  
Y. P. Peter Di
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Binding ◽  
Signaling Pathways ◽  
Tobacco Smoke ◽  
Mapk Signaling ◽  
Regulation Of Transcription ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Mapk Signaling Pathways

Activation and regulation of transcription factors (TFs) are the major mechanisms regulating changes in gene expression upon environmental exposure. Tobacco smoke (TS) is a complex mixture of chemicals, each of which could act through different signal cascades, leading to the regulation of distinct TFs and alterations in subsequent gene expression. We proposed that TS exposure affects inflammatory gene expression at the transcriptional level by modulating the DNA binding activities of TFs. To investigate transcriptional regulation upon TS exposure, a protein/DNA array was applied to screen TFs that are affected by TS exposure. This array-based screening allowed us to simultaneously detect 244 different TFs. Our results indicated that multiple TFs were rapidly activated upon TS exposure. DNA-binding activity of differentially expressed TFs was confirmed by EMSA. Our results showed that at least 20 TFs displayed more than twofold expressional changes after smoke treatment. Ten smoke-induced TFs, including NF-κB, VDR, ISRE, and RSRFC4, were involved in MAPK signaling pathways. The NF-κB family, which is involved in inflammation-induced gene activation, was selected for further study to characterize TS exposure-induced transcriptional activation. Western blot analysis and immunofluorescence microscopy indicated that TS exposure induced phosphorylation of IκB and translocation of NF-κB p65/p50 heterodimers into the nucleus. This activity was abrogated by the MAPK inhibitors PD98059 and U0126. Our results confirmed that activation of MAPK signaling pathways by TS exposure increased transcriptional activity of NF-κB. These data provide a potential mechanism for TS-induced inflammatory gene expression.

scholarly journals Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes

2016 ◽  
Vol 76 (1) ◽  
pp. 277-285 ◽  
Author(s):  
Chiara Angiolilli ◽  
Pawel A Kabala ◽  
Aleksander M Grabiec ◽  
Iris M Van Baarsen ◽  
Bradley S Ferguson ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Dna Binding ◽  
Histone Deacetylase ◽  
Type I ◽  
Type I Ifn ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Inducible Genes ◽  
Fibroblast Like Synoviocytes

ObjectivesNon-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblast-like synoviocytes (FLS).MethodsRA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)-α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quantitative PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays.ResultsHDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN production and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11.ConclusionsInhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN production in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.

scholarly journals Pericentromeric noncoding RNA changes DNA binding of CTCF and inflammatory gene expression in senescence and cancer

2021 ◽  
Vol 118 (35) ◽  
pp. e2025647118
Author(s):  
Kenichi Miyata ◽  
Yoshinori Imai ◽  
Satoshi Hori ◽  
Mika Nishio ◽  
Tze Mun Loo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Cellular Senescence ◽  
Noncoding Rna ◽  
Repetitive Sequences ◽  
Global Gene Expression ◽  
Chromatin Organization ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Age Related

Cellular senescence causes a dramatic alteration of chromatin organization and changes the gene expression profile of proinflammatory factors, thereby contributing to various age-related pathologies through the senescence-associated secretory phenotype (SASP). Chromatin organization and global gene expression are maintained by the CCCTC-binding factor (CTCF); however, the molecular mechanism underlying CTCF regulation and its association with SASP gene expression remains unclear. We discovered that noncoding RNA (ncRNA) derived from normally silenced pericentromeric repetitive sequences directly impairs the DNA binding of CTCF. This CTCF disturbance increases the accessibility of chromatin and activates the transcription of SASP-like inflammatory genes, promoting malignant transformation. Notably, pericentromeric ncRNA was transferred into surrounding cells via small extracellular vesicles acting as a tumorigenic SASP factor. Because CTCF blocks the expression of pericentromeric ncRNA in young cells, the down-regulation of CTCF during cellular senescence triggers the up-regulation of this ncRNA and SASP-related inflammatory gene expression. In this study, we show that pericentromeric ncRNA provokes chromosomal alteration by inhibiting CTCF, leading to a SASP-like inflammatory response in a cell-autonomous and non–cell-autonomous manner and thus may contribute to the risk of tumorigenesis during aging.

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