Cholesterol is required for transcriptional repression by BASP1

Area of Science:

• Molecular Biology
• Epigenetics
• Cell Biology

Background:

• Lipids, including cholesterol, are found in the cell nucleus and influence gene regulation.
• Cholesterol's role in specific transcriptional responses remains unclear, despite its association with chromatin.

Purpose of the Study:

• To investigate the role of the lipidated Wilms tumor 1 (WT1) transcriptional corepressor, BASP1, in nuclear cholesterol regulation.
• To elucidate the mechanism by which BASP1 interacts with cholesterol and affects gene transcription.

Main Methods:

• Investigated the interaction between BASP1 and cholesterol using biochemical assays.
• Utilized gene promoter analysis to determine cholesterol recruitment by BASP1.
• Employed gene editing (mutation of BASP1) and pharmacological inhibition of cholesterol biosynthesis.
• Assessed effects on chromatin remodeling and gene transcription controlling cell differentiation.

Main Results:

• BASP1 directly interacts with cholesterol in the cell nucleus via a conserved motif.
• BASP1 recruits cholesterol to the promoter regions of WT1 target genes.
• Disrupting the BASP1-cholesterol interaction or inhibiting cholesterol synthesis impairs BASP1's repressor function.
• The BASP1-cholesterol interaction is essential for BASP1-mediated chromatin remodeling and regulating cell differentiation transcription programs.

Conclusions:

• BASP1 acts as a nuclear cholesterol sensor and targets cholesterol to specific gene promoters.
• This mechanism highlights a novel pathway for gene-specific cholesterol regulation in transcriptional repression.
• The BASP1-cholesterol interaction is critical for controlling gene expression programs involved in cell differentiation.