Cholesterol is required for transcriptional repression by BASP1

Amy E Dey; Samantha Carrera; Anna F Fleming; Abigail Roberts; Alice Sherrard; Eneda Toska; Alex Moorhouse; Kathryn F Medler; Stefan G E Roberts

doi:10.1073/pnas.2101671118

Cholesterol is required for transcriptional repression by BASP1

Amy E Dey, Samantha Carrera, Anna F Fleming, Abigail Roberts, Alice Sherrard, Eneda Toska, Alex Moorhouse, Kathryn F Medler, Stefan G E Roberts^*

^*Corresponding author for this work

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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 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.

Original language	English
Article number	e2101671118
Number of pages	11
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	29
Early online date	15 Jul 2021
DOIs	https://doi.org/10.1073/pnas.2101671118
Publication status	Published - 20 Jul 2021

Bibliographical note

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.

Keywords

BASP1
WT1
cholesterol
transcription
chromatin

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The regulation of Wilms' tumour 1 by phospholipid
Roberts, S. G. E. (Principal Investigator)
1/05/13 → 1/05/16
Project: Research

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title = "Cholesterol is required for transcriptional repression by BASP1",

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 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. ",

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author = "Dey, {Amy E} and Samantha Carrera and Fleming, {Anna F} and Abigail Roberts and Alice Sherrard and Eneda Toska and Alex Moorhouse and Medler, {Kathryn F} and Roberts, {Stefan G E}",

note = "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: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",

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AU - Moorhouse, Alex

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.

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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 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.

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 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.

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DO - 10.1073/pnas.2101671118

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Cholesterol is required for transcriptional repression by BASP1

Abstract

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The regulation of Wilms' tumour 1 by phospholipid

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