TY - JOUR
T1 - Cholesterol is required for transcriptional repression by BASP1
AU - Loats, Amy E.
AU - Carrera, Samantha
AU - Fleming, Anna F.
AU - Roberts, Abigail R.E.
AU - Sherrard, Alice
AU - Toska, Eneda
AU - Moorhouse, Alexander J.
AU - Medler, Kathryn F.
AU - Roberts, Stefan G.E.
N1 - Funding 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).
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
PY - 2021/7/20
Y1 - 2021/7/20
N2 - 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.
AB - 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.
KW - BASP1 | WT1 | cholesterol | transcription | chromatin
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U2 - 10.1073/pnas.2101671118
DO - 10.1073/pnas.2101671118
M3 - Article
C2 - 34266955
AN - SCOPUS:85110486329
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
M1 - e2101671118
ER -