Cholesterol is required for transcriptional repression by BASP1

Amy E. Loats, Samantha Carrera, Anna F. Fleming, Abigail R. E. Roberts, Alice Sherrard, Eneda Toska, Alexander J. Moorhouse, Kathryn F Medler, Stefan G. E. Roberts

Research output: Contribution to journalArticlepeer-review

Abstract

Lipids are present within the cell nucleus, where they engage with factors involved in gene regulation. Cholesterol associates with chromatin in vivo and stimulates nucleosome packing in vitro, but its effects on specific transcriptional responses are not clear. Here, we show that the lipidated Wilms tumor 1 (WT1) transcriptional corepressor, brain acid soluble protein 1 (BASP1), interacts with cholesterol in the cell nucleus through a conserved cholesterol interaction motif. We demonstrate that BASP1 directly recruits cholesterol to the promoter region of WT1 target genes. Mutation of BASP1 to ablate its interaction with cholesterol or the treatment of cells with drugs that block cholesterol biosynthesis inhibits the transcriptional repressor function of BASP1. We find that the BASP1-cholesterol interaction is required for BASP1-dependent chromatin remodeling and the direction of transcription programs that control cell differentiation. Our study uncovers a mechanism for gene-specific targeting of cholesterol where it is required to mediate transcriptional repression.

Original languageEnglish
Article numbere2101671118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number29
DOIs
Publication statusPublished - 15 Jul 2021

Keywords

  • Cell Nucleus/metabolism
  • Cholesterol/metabolism
  • Down-Regulation
  • Humans
  • K562 Cells
  • Membrane Proteins/genetics
  • Nerve Tissue Proteins/genetics
  • Promoter Regions, Genetic
  • Protein Binding
  • Repressor Proteins/genetics
  • Transcription, Genetic

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