Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Pakavarin Louphrasitthiphol; Robert Siddaway; Alessia Loffreda; Vivian Pogenberg; Hans Friedrichsen; Alexander Schepsky; Zhiqiang Zeng; Min Lu; Thomas Strub; Rasmus Freter; Richard Lisle; Eda Suer; Benjamin Thomas; Benjamin Schuster-Böckler; Panagis Filippakopoulos; Mark Middleton; Xin Lu; E. Elizabeth Patton; Irwin Davidson; Jean Philippe Lambert; Matthias Wilmanns; Eiríkur Steingrímsson; Davide Mazza; Colin R. Goding

doi:10.1016/j.molcel.2020.05.025

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

Pakavarin Louphrasitthiphol, Robert Siddaway, Alessia Loffreda, Vivian Pogenberg, Hans Friedrichsen, Alexander Schepsky, Zhiqiang Zeng, Min Lu, Thomas Strub, Rasmus Freter, Richard Lisle, Eda Suer, Benjamin Thomas, Benjamin Schuster-Böckler, Panagis Filippakopoulos, Mark Middleton, Xin Lu, E. Elizabeth Patton, Irwin Davidson, Jean Philippe LambertMatthias Wilmanns, Eiríkur Steingrímsson, Davide Mazza, Colin R. Goding

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

Abstract

It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.

Original language	English
Pages (from-to)	472-487.e10
Journal	Molecular Cell
Volume	79
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2020.05.025
Publication status	Published - Aug 6 2020

Keywords

acetylation
bHLH-LZ
DNA-binding affinity
E-box
melanocyte
melanoma
MITF
transcription factor

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.05.025

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Louphrasitthiphol, P., Siddaway, R., Loffreda, A., Pogenberg, V., Friedrichsen, H., Schepsky, A., Zeng, Z., Lu, M., Strub, T., Freter, R., Lisle, R., Suer, E., Thomas, B., Schuster-Böckler, B., Filippakopoulos, P., Middleton, M., Lu, X., Patton, E. E., Davidson, I., ... Goding, C. R. (2020). Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution. Molecular Cell, 79(3), 472-487.e10. https://doi.org/10.1016/j.molcel.2020.05.025

Louphrasitthiphol, P, Siddaway, R, Loffreda, A, Pogenberg, V, Friedrichsen, H, Schepsky, A, Zeng, Z, Lu, M, Strub, T, Freter, R, Lisle, R, Suer, E, Thomas, B, Schuster-Böckler, B, Filippakopoulos, P, Middleton, M, Lu, X, Patton, EE, Davidson, I, Lambert, JP, Wilmanns, M, Steingrímsson, E, Mazza, D & Goding, CR 2020, 'Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution', Molecular Cell, vol. 79, no. 3, pp. 472-487.e10. https://doi.org/10.1016/j.molcel.2020.05.025

@article{4b5f980110fe4da39f8313f7b963bcf4,

title = "Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution",

abstract = "It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.",

keywords = "acetylation, bHLH-LZ, DNA-binding affinity, E-box, melanocyte, melanoma, MITF, transcription factor",

author = "Pakavarin Louphrasitthiphol and Robert Siddaway and Alessia Loffreda and Vivian Pogenberg and Hans Friedrichsen and Alexander Schepsky and Zhiqiang Zeng and Min Lu and Thomas Strub and Rasmus Freter and Richard Lisle and Eda Suer and Benjamin Thomas and Benjamin Schuster-B{\"o}ckler and Panagis Filippakopoulos and Mark Middleton and Xin Lu and Patton, {E. Elizabeth} and Irwin Davidson and Lambert, {Jean Philippe} and Matthias Wilmanns and Eir{\'i}kur Steingr{\'i}msson and Davide Mazza and Goding, {Colin R.}",

note = "Funding Information: The Piggybac vectors were provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G., R.F., B.S.-B., E. Suer, and X.L. ), Cancer Research UK (CRUK) grant number C38302/A12981 , through a CRUK Oxford Centre Prize DPhil Studentship (HF), the Medical Research Council (R.S., Z.Z., P.F.; MR/N010051/1 and E.E.P.; MC_UU_00007/9 ), L{\textquoteright}Oreal-Melanoma Research Alliance 401181 (E.E.P.), the Harry J. Lloyd Trust (R.S.), the Wellcome Trust (P.F. and A.S.), the Postdoc Fund of the University of Iceland (A.S.), the Oxford Biomedical Research Centre (R.L.), the Research Fund of Iceland (E.S.), a European Research Consolidator Award ( ZF-MEL-CHEMBIO 648489 ) (E.E.P.), the CNRS , INSERM , the Ligue Nationale Contre le Cancer , the Institut National du Cancer ( INCa ), the ANR-10-LABX-0030-INRT French state fund (I.D.), and a Junior 1 salary award from the Fonds de Recherche du Qu{\'e}bec-Sant{\'e} ( FRQ-S ). This work was also funded by operating grants from the Cancer Research Society (J.-P.L.), the Fondazione Cariplo (A.L. and D.M.; 2014-1157 ), and the Italian Cancer Research Association ( AIRC ; IG2018- 21897 ; D.M.). I.D. is an “{\'e}quipe labellis{\'e}e” of the Ligue Nationale Contre le Cancer . Funding Information: The Piggybac vectors were provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G. R.F. B.S.-B. E. Suer, and X.L. ), Cancer Research UK (CRUK) grant number C38302/A12981, through a CRUK Oxford Centre Prize DPhil Studentship (HF), the Medical Research Council (R.S. Z.Z. P.F.; MR/N010051/1 and E.E.P.; MC_UU_00007/9), L'Oreal-Melanoma Research Alliance 401181 (E.E.P.), the Harry J. Lloyd Trust (R.S.), the Wellcome Trust (P.F. and A.S.), the Postdoc Fund of the University of Iceland (A.S.), the Oxford Biomedical Research Centre (R.L.), the Research Fund of Iceland (E.S.), a European Research Consolidator Award (ZF-MEL-CHEMBIO 648489) (E.E.P.), the CNRS, INSERM, the Ligue Nationale Contre le Cancer, the Institut National du Cancer (INCa), the ANR-10-LABX-0030-INRT French state fund (I.D.), and a Junior 1 salary award from the Fonds de Recherche du Qu?bec-Sant? (FRQ-S). This work was also funded by operating grants from the Cancer Research Society (J.-P.L.), the Fondazione Cariplo (A.L. and D.M.; 2014-1157), and the Italian Cancer Research Association (AIRC; IG2018- 21897; D.M.). I.D. is an ??quipe labellis?e? of the Ligue Nationale Contre le Cancer. Conceptualization, C.R.G.; Supervision, C.R.G. E. Suer, I.D. T.S. E. Steingr?msson, E.E.P. D.M. and M.W.; Visualization, P.L. R.S. H.F. A.L. A.S. P.F.-S. Z.Z. R.F. M.L. P.F. R.L. E. Suer, P.L. J.-P.L. V.P. and C.R.G.; Formal Analysis, P.L. R.S. B.T. B.S.-B. M.L. A.L. D.M. and V.P.; Investigation, P.L. R.S. H.F. A.L. A.S. Z.Z. E. Suer, M.L. R.F. R.L. B.T. J.-P.L. and V.P.; Writing ? Original Draft, C.R.G. R.S. and P.L.; Writing ? Review & Editing, C.R.G. R.S. P.L. and D.M.; Funding Acquisition, C.R.G. E. Steingr?msson, X.L. E.E.P. M.M. I.D. P.F. B.T. M.W. and D.M. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = aug,

day = "6",

doi = "10.1016/j.molcel.2020.05.025",

language = "English",

volume = "79",

pages = "472--487.e10",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

AU - Louphrasitthiphol, Pakavarin

AU - Siddaway, Robert

AU - Loffreda, Alessia

AU - Pogenberg, Vivian

AU - Friedrichsen, Hans

AU - Schepsky, Alexander

AU - Zeng, Zhiqiang

AU - Lu, Min

AU - Strub, Thomas

AU - Freter, Rasmus

AU - Lisle, Richard

AU - Suer, Eda

AU - Thomas, Benjamin

AU - Schuster-Böckler, Benjamin

AU - Filippakopoulos, Panagis

AU - Middleton, Mark

AU - Lu, Xin

AU - Patton, E. Elizabeth

AU - Davidson, Irwin

AU - Lambert, Jean Philippe

AU - Wilmanns, Matthias

AU - Steingrímsson, Eiríkur

AU - Mazza, Davide

AU - Goding, Colin R.

N1 - Funding Information: The Piggybac vectors were provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G., R.F., B.S.-B., E. Suer, and X.L. ), Cancer Research UK (CRUK) grant number C38302/A12981 , through a CRUK Oxford Centre Prize DPhil Studentship (HF), the Medical Research Council (R.S., Z.Z., P.F.; MR/N010051/1 and E.E.P.; MC_UU_00007/9 ), L’Oreal-Melanoma Research Alliance 401181 (E.E.P.), the Harry J. Lloyd Trust (R.S.), the Wellcome Trust (P.F. and A.S.), the Postdoc Fund of the University of Iceland (A.S.), the Oxford Biomedical Research Centre (R.L.), the Research Fund of Iceland (E.S.), a European Research Consolidator Award ( ZF-MEL-CHEMBIO 648489 ) (E.E.P.), the CNRS , INSERM , the Ligue Nationale Contre le Cancer , the Institut National du Cancer ( INCa ), the ANR-10-LABX-0030-INRT French state fund (I.D.), and a Junior 1 salary award from the Fonds de Recherche du Québec-Santé ( FRQ-S ). This work was also funded by operating grants from the Cancer Research Society (J.-P.L.), the Fondazione Cariplo (A.L. and D.M.; 2014-1157 ), and the Italian Cancer Research Association ( AIRC ; IG2018- 21897 ; D.M.). I.D. is an “équipe labellisée” of the Ligue Nationale Contre le Cancer . Funding Information: The Piggybac vectors were provided by Kazuhiro Murakami (RIKEN, Kobe, Japan). This work was funded by the Ludwig Institute for Cancer Research (C.R.G. R.F. B.S.-B. E. Suer, and X.L. ), Cancer Research UK (CRUK) grant number C38302/A12981, through a CRUK Oxford Centre Prize DPhil Studentship (HF), the Medical Research Council (R.S. Z.Z. P.F.; MR/N010051/1 and E.E.P.; MC_UU_00007/9), L'Oreal-Melanoma Research Alliance 401181 (E.E.P.), the Harry J. Lloyd Trust (R.S.), the Wellcome Trust (P.F. and A.S.), the Postdoc Fund of the University of Iceland (A.S.), the Oxford Biomedical Research Centre (R.L.), the Research Fund of Iceland (E.S.), a European Research Consolidator Award (ZF-MEL-CHEMBIO 648489) (E.E.P.), the CNRS, INSERM, the Ligue Nationale Contre le Cancer, the Institut National du Cancer (INCa), the ANR-10-LABX-0030-INRT French state fund (I.D.), and a Junior 1 salary award from the Fonds de Recherche du Qu?bec-Sant? (FRQ-S). This work was also funded by operating grants from the Cancer Research Society (J.-P.L.), the Fondazione Cariplo (A.L. and D.M.; 2014-1157), and the Italian Cancer Research Association (AIRC; IG2018- 21897; D.M.). I.D. is an ??quipe labellis?e? of the Ligue Nationale Contre le Cancer. Conceptualization, C.R.G.; Supervision, C.R.G. E. Suer, I.D. T.S. E. Steingr?msson, E.E.P. D.M. and M.W.; Visualization, P.L. R.S. H.F. A.L. A.S. P.F.-S. Z.Z. R.F. M.L. P.F. R.L. E. Suer, P.L. J.-P.L. V.P. and C.R.G.; Formal Analysis, P.L. R.S. B.T. B.S.-B. M.L. A.L. D.M. and V.P.; Investigation, P.L. R.S. H.F. A.L. A.S. Z.Z. E. Suer, M.L. R.F. R.L. B.T. J.-P.L. and V.P.; Writing ? Original Draft, C.R.G. R.S. and P.L.; Writing ? Review & Editing, C.R.G. R.S. P.L. and D.M.; Funding Acquisition, C.R.G. E. Steingr?msson, X.L. E.E.P. M.M. I.D. P.F. B.T. M.W. and D.M. The authors declare no competing interests. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/8/6

Y1 - 2020/8/6

N2 - It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.

AB - It is widely assumed that decreasing transcription factor DNA-binding affinity reduces transcription initiation by diminishing occupancy of sequence-specific regulatory elements. However, in vivo transcription factors find their binding sites while confronted with a large excess of low-affinity degenerate motifs. Here, using the melanoma lineage survival oncogene MITF as a model, we show that low-affinity binding sites act as a competitive reservoir in vivo from which transcription factors are released by mitogen-activated protein kinase (MAPK)-stimulated acetylation to promote increased occupancy of their regulatory elements. Consequently, a low-DNA-binding-affinity acetylation-mimetic MITF mutation supports melanocyte development and drives tumorigenesis, whereas a high-affinity non-acetylatable mutant does not. The results reveal a paradoxical acetylation-mediated molecular clutch that tunes transcription factor availability via genome-wide redistribution and couples BRAF to tumorigenesis. Our results further suggest that p300/CREB-binding protein-mediated transcription factor acetylation may represent a common mechanism to control transcription factor availability.

KW - acetylation

KW - bHLH-LZ

KW - DNA-binding affinity

KW - E-box

KW - melanocyte

KW - melanoma

KW - MITF

KW - transcription factor

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DO - 10.1016/j.molcel.2020.05.025

M3 - Article

C2 - 32531202

AN - SCOPUS:85086922593

VL - 79

SP - 472-487.e10

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -

Tuning Transcription Factor Availability through Acetylation-Mediated Genomic Redistribution

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Keywords

ASJC Scopus subject areas

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