TRPM3-Induced Gene Transcription Is under Epigenetic Control

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Transient receptor potential M3 (TRPM3) cation channels play a role in various biological processes, including gene transcription.
• TRPM3 channel stimulation by pregnenolone sulfate activates transcription factors and involves coregulator proteins for chromatin remodeling.
• The precise mechanisms of TRPM3-induced gene transcription, particularly the role of histone acetylation, remain to be fully elucidated.

Purpose of the Study:

• To investigate whether TRPM3-induced gene transcription necessitates coactivators that modify histone acetylation patterns.
• To determine the involvement of histone acetyltransferases (HATs) CBP and p300 in TRPM3-mediated transcription.
• To analyze the role of bromodomain proteins, specifically BET family proteins, in TRPM3 signaling.

Main Methods:

• Utilized compound A485, a specific inhibitor of CBP and p300 histone acetyltransferases.
• Employed JQ1, an inhibitor targeting bromodomain and extra terminal domain (BET) family proteins.
• Assessed the impact of these inhibitors on AP-1 and CREB-regulated gene transcription, as well as the activity of transcription factors c-Fos and Elk-1.

Main Results:

• Both A485 and JQ1 significantly attenuated the activation of AP-1 and CREB-regulated gene transcription upon TRPM3 channel stimulation.
• Inhibition of CBP/p300 and BET proteins reduced the transcriptional activation potential of c-Fos and Elk-1.
• Transcriptional upregulation of the interleukin-8 gene was diminished by A485 and JQ1, highlighting the role in controlling proinflammatory cytokine expression.

Conclusions:

• TRPM3-induced signaling pathways critically depend on transcriptional coactivators, including CBP/p300.
• Acetyl-lysine-bound bromodomain proteins are essential components in the TRPM3-mediated gene transcription process.
• These findings reveal a novel mechanism linking TRPM3 channels to epigenetic regulation of gene expression, particularly for inflammatory responses.