JNK phosphorylation of BRD4 triggers its transition from a chromatin modifier into a transcriptional activator

– Poster session IV
2:30 – 4:00 p.m.

FAES Terrace

NCI

MOLBIO-15

Authors

  • DN Devaiah
  • AK Singh
  • J Mu
  • Q Chen
  • D Meerzaman
  • DS Singer

Abstract

BRD4 is a key regulatory factor controlling multiple cancers and cellular stress responses. It regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities respectively. BRD4 is primarily a chromatin bound protein but is released from the chromatin to recruit and regulate crucial elements of the transcriptional machinery during periods of activated transcription such as immune and inflammatory responses or cancer progression. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that the JNK kinase directly interacts with BRD4 and phosphorylates it specifically at Ser1117, Thr1186 and Thr1212, triggering BRD4 release from chromatin genome wide. Activation of JNK kinase by a broad range of stimuli causes the release of BRD4 from chromatin. JNK phosphorylated BRD4 is dephosphorylated by the PP4 phosphatase in the nucleoplasm, allowing its interaction with RNA Pol II at transcriptionally active sites. JNK phosphorylation of BRD4 blocks its chromatin regulatory HAT function and activates its transcription-enhancing kinase function. Accordingly, JNK activation leads to significantly elevated transcription of BRD4 regulated immune and inflammatory response genes in a manner dependent on the presence of the three JNK phospho-sites on BRD4. JNK phosphorylation of BRD4 is involved in biological processes such as T-cell activation and is required for epithelial to mesenchymal transition (EMT) during cancer progression. These finding thus characterize a hitherto unknown mechanism that allows BRD4 to transition from a chromatin to transcriptional regulator during immune/inflammatory response and EMT.

Scientific Focus Area: Molecular Biology and Biochemistry

This page was last updated on Monday, September 25, 2023

2023 NIH Research Festival Agenda

2023 NIH Research Festival Poster Abstracts