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| Status |
Public on Feb 15, 2024 |
| Title |
Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.
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| Overall design |
Samples were analyzed by duplicate using biological repliques. Untreated and unstimulated cells were used as control cells. Cells stimulated with Thapsigargin were used to activate ER stress. Analyzed conditions were: untreated and unstimulated cells. cells estimulated with thapsigargin, cells stimulated with thapsigargin and treated with JQ1, cells knocked for XBP1 gene and stimulated with thapsigargin and cells knocked for ATF4 gene and stimulated with thapsigargin
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| Web link |
https://www.ijbs.com/v20p1547
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| Contributor(s) |
Diaz-Bulnes P, Rodriguez RM, Banon-Maneus E, Saiz ML, Corte-Iglesias V, Ramirez MJ, Lazo-Rodriguez M, Tamargo Lopez I, Rodrigues Diez R, Diaz-Corte C, Ruiz-Ortega M, Diekmann F, Aransay AM, López-Larrea C, Suarez Alvarez B |
| Citation(s) |
38481808 |
| Submission date |
Nov 02, 2022 |
| Last update date |
Mar 20, 2024 |
| Contact name |
Ana Maria Aransay |
| E-mail(s) |
amaransay@cicbiogune.es
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| Phone |
0034944061325
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| Organization name |
CIC bioGUNE
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| Department |
Genome Analysis Platform
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| Street address |
Parque tecnologico de Bizkaia, Building 801-A
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| City |
Derio |
| State/province |
BIZKAIA |
| ZIP/Postal code |
48160 |
| Country |
Spain |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (10)
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| Relations |
| BioProject |
PRJNA896949 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE217103_HCFIS-18A_RawCounts_STAR.txt.gz |
558.1 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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