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| Status |
Public on Sep 16, 2024 |
| Title |
Toggling of BRD4 functions is triggered through its phosphorylation by JNK [RNAseq-JQ1] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. It regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.
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| Overall design |
This RNA-seq analysis is aimed at identifying genome-wide differential gene expression when HCT116 cells are treated JQ1, a small molecule BET inhibitor that blocks BRD4 from binding chromatin. The analysis includes samples where untransfected (E) and wild type BRD4 transfected (B) HCT116 cells are treated with or without 500nM JQ1 (J) for 18 hrs. The analysis was done to compare the DEGs from JQ1 treated cells with the DEGs identified upon the release of BRD4 from chromatin through JNK activiation.
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| Contributor(s) |
Ballachanda DN, Singh AK, Mu J, Chen Q, Meerzaman D, Singer D |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Jun 26, 2024 |
| Last update date |
Sep 16, 2024 |
| Contact name |
Dinah S. Singer |
| E-mail(s) |
dinah.singer@nih.gov
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| Phone |
301-496-9097
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| Organization name |
National Cancer Institute
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| Department |
Division of Cancer Biology
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| Street address |
Building 10, Room 4B-17
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| GSM8354205 |
Control empty vector transfected cells, biol HCT116 rep1 |
| GSM8354206 |
Control empty vector transfected cells, biol HCT116 rep2 |
| GSM8354207 |
Control empty vector transfected cells, biol HCT116 rep3 |
| GSM8354208 |
Untreated BRD4 transfected cells, biol HCT116 rep 1 |
| GSM8354209 |
Untreated BRD4 transfected cells, biol HCT116 rep 2 |
| GSM8354210 |
Untreated BRD4 transfected cells, biol HCT116 rep 3 |
| GSM8354211 |
Control empty vector transfected cells, JQ1 treated ,biol HCT116 rep1 |
| GSM8354212 |
Control empty vector transfected cells, JQ1 treated ,biol HCT116 rep2 |
| GSM8354213 |
Control empty vector transfected cells, JQ1 treated ,biol HCT116 rep3 |
| GSM8354214 |
BRD4 transfected cells, JQ1 treated ,biol HCT116 rep1 |
| GSM8354215 |
BRD4 transfected cells, JQ1 treated ,biol HCT116 rep2 |
| GSM8354216 |
BRD4 transfected cells, JQ1 treated ,biol HCT116 rep3 |
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| This SubSeries is part of SuperSeries: |
| GSE252982 |
Toggling of BRD4 functions is triggered through its phosphorylation by JNK. |
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| Relations |
| BioProject |
PRJNA1128696 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE270887_RAW.tar |
1.3 Mb |
(http)(custom) |
TAR (of TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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