Intercalated Motifs Contribute to Transcription Regulation in an Acidosis Model

Area of Science:

• Genomics
• Molecular Biology
• Biochemistry

Background:

• Intercalated motifs (iMs) are pH-sensitive DNA structures found in cytosine-rich genomic regions.
• Their role in gene regulation, particularly under acidosis, remains largely uncharacterized.

Purpose of the Study:

• To investigate the impact of iMs on the transcription of early response genes under varying pH conditions.
• To explore the potential of iM-targeting ligands to modulate gene expression and counteract acidosis-specific effects.

Main Methods:

• Luciferase-based reporter gene assays were employed to assess transcriptional activity.
• Experiments were conducted under normal, acidic, and ligand-treated conditions to favor or disfavor iM formation.
• Optical methods and molecular modeling were used to verify pH effects and elucidate ligand interactions.

Main Results:

• Acidification led to iM formation, which generally repressed reporter gene expression.
• This repression was reversible upon treatment with specific iM-destabilizing ligands.
• An anticancer drug candidate demonstrated efficacy in reversing iM-mediated repression.

Conclusions:

• Intercalated motifs play a role in transcriptional repression under acidic conditions, relevant to acidosis.
• Targeting iMs with small molecules presents a potential therapeutic avenue for managing acidosis-associated pathologies.
• Further research into iM-ligand interactions could yield novel treatments for diseases involving altered pH homeostasis.