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 WT1 transcriptional corepressor, 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 inhibit 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.
|Number of pages||11|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Early online date||15 Jul 2021|
|Publication status||Published - 20 Jul 2021|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We are grateful to Adrian Bunzel for help with fluorimetry and to Khamal Ampah for help with phase imaging. This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) to S.G.E.R. (BB/T001925/1), Medical Research Council (MRC) to S.G.E.R. (MR/K001027/1), and NIH to K.F.M. and S.G.E.R. (1R01GM098609). A.E.L. was supported by a Wellcome Trust PhD Studentship for the Dynamic Cell Biology program (083474).
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