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A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1

Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs fo...

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Autores principales: Si, Yang, Bon, Corentin, Barbachowska, Magdalena, Cadet-Daniel, Veronique, Jallet, Corinne, Soresinetti, Laura, Boullé, Mikaël, Duchateau, Magalie, Matondo, Mariette, Agou, Fabrice, Halby, Ludovic, Arimondo, Paola B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985137/
https://www.ncbi.nlm.nih.gov/pubmed/35441144
http://dx.doi.org/10.1039/d1cb00095k
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author Si, Yang
Bon, Corentin
Barbachowska, Magdalena
Cadet-Daniel, Veronique
Jallet, Corinne
Soresinetti, Laura
Boullé, Mikaël
Duchateau, Magalie
Matondo, Mariette
Agou, Fabrice
Halby, Ludovic
Arimondo, Paola B.
author_facet Si, Yang
Bon, Corentin
Barbachowska, Magdalena
Cadet-Daniel, Veronique
Jallet, Corinne
Soresinetti, Laura
Boullé, Mikaël
Duchateau, Magalie
Matondo, Mariette
Agou, Fabrice
Halby, Ludovic
Arimondo, Paola B.
author_sort Si, Yang
collection PubMed
description Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs form multiprotein complexes that in concert regulate gene expression. To probe epigenetic protein complexes regulation in cells, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries simultaneously on multiple histone marks inside cells. By this approach, we identified that compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L. Based on this interaction, we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger inhibition of cell proliferation and increase in apoptosis, indicating that our approach identifies possible effective synergistic drug combinations.
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spelling pubmed-89851372022-04-18 A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1 Si, Yang Bon, Corentin Barbachowska, Magdalena Cadet-Daniel, Veronique Jallet, Corinne Soresinetti, Laura Boullé, Mikaël Duchateau, Magalie Matondo, Mariette Agou, Fabrice Halby, Ludovic Arimondo, Paola B. RSC Chem Biol Chemistry Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs form multiprotein complexes that in concert regulate gene expression. To probe epigenetic protein complexes regulation in cells, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries simultaneously on multiple histone marks inside cells. By this approach, we identified that compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L. Based on this interaction, we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger inhibition of cell proliferation and increase in apoptosis, indicating that our approach identifies possible effective synergistic drug combinations. RSC 2022-02-22 /pmc/articles/PMC8985137/ /pubmed/35441144 http://dx.doi.org/10.1039/d1cb00095k Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Si, Yang
Bon, Corentin
Barbachowska, Magdalena
Cadet-Daniel, Veronique
Jallet, Corinne
Soresinetti, Laura
Boullé, Mikaël
Duchateau, Magalie
Matondo, Mariette
Agou, Fabrice
Halby, Ludovic
Arimondo, Paola B.
A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title_full A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title_fullStr A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title_full_unstemmed A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title_short A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1
title_sort novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between dot1l and carm1
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985137/
https://www.ncbi.nlm.nih.gov/pubmed/35441144
http://dx.doi.org/10.1039/d1cb00095k
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