Transcription factor LSF-DNMT1 complex dissociation by FQI1 leads to aberrant DNA methylation and gene expression

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Research

Background:

• Hepatocellular carcinoma (HCC) is promoted by the transcription factor LSF.
• Factor quinolinone inhibitor 1 (FQI1) inhibits LSF DNA-binding activity and has anti-proliferative effects.

Purpose of the Study:

• To investigate the interaction between LSF, DNMT1, and UHRF1.
• To elucidate the mechanism by which FQI1 affects DNA methylation and gene expression in HCC.

Main Methods:

• In vivo and in vitro binding assays to study LSF, DNMT1, and UHRF1 interactions.
• Cell culture experiments treated with FQI1 to assess global and regional DNA methylation.
• Analysis of differentially methylated regions (DMRs) and their correlation with gene expression.

Main Results:

• LSF directly binds to DNMT1 and UHRF1, enhancing DNMT1 activity.
• FQI1 inhibits LSF-DNMT1-UHRF1 complex formation, leading to global aberrant CpG methylation.
• FQI1 treatment alters gene expression through widespread DNA methylation changes in DMRs near transcription start sites and within genes.

Conclusions:

• FQI1 disrupts the DNMT1-LSF complex, revealing a novel epigenetic regulatory mechanism.
• FQI1-induced aberrant DNA methylation impacts gene expression and cell cycle progression in HCC.
• This study highlights a new therapeutic strategy targeting epigenetic alterations in cancer.