HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia
Sebastian Gregoricchio
(1, 2, 3)
,
Lélia Polit
(4)
,
Michela Esposito
(1, 2)
,
Jérémy Berthelet
(5)
,
Laure Delestré
(1, 2)
,
Emilie Evanno
(6)
,
M’boyba Diop
(1, 2)
,
Isabelle Gallais
(6)
,
Hanna Aleth
(7)
,
Mathilde Poplineau
(8, 9)
,
Wilbert Zwart
(3)
,
Frank Rosenbauer
(7)
,
Fernando Rodrigues-Lima
(5)
,
Estelle Duprez
(8, 9)
,
Valentina Boeva
(4, 10)
,
Christel Guillouf
(1, 2)
1
Dynamo -
Dynamique moléculaire de la transformation hématopoïétique
2 IGR - Institut Gustave Roussy
3 NKI - Netherlands Cancer Institute
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
6 U830 - Unité de génétique et biologie des cancers
7 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
8 CRCM - Centre de Recherche en Cancérologie de Marseille
9 IPC - Institut Paoli-Calmettes
10 D-INFK - Department of Computer Science [ETH Zürich]
2 IGR - Institut Gustave Roussy
3 NKI - Netherlands Cancer Institute
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
6 U830 - Unité de génétique et biologie des cancers
7 WWU - Westfälische Wilhelms-Universität Münster = University of Münster
8 CRCM - Centre de Recherche en Cancérologie de Marseille
9 IPC - Institut Paoli-Calmettes
10 D-INFK - Department of Computer Science [ETH Zürich]
Sebastian Gregoricchio
- Fonction : Auteur
- PersonId : 1176690
- ORCID : 0000-0001-9209-5403
Fernando Rodrigues-Lima
- Fonction : Auteur
- PersonId : 1176691
- ORCID : 0000-0002-1081-4767
Estelle Duprez
- Fonction : Auteur
- PersonId : 11810
- IdHAL : eduprez
- ORCID : 0000-0003-3810-5740
- IdRef : 139804757
Christel Guillouf
- Fonction : Auteur
- PersonId : 741361
- IdHAL : christel-guillouf
- ORCID : 0000-0001-7013-3149
Résumé
Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Résumé |
en
Although originally described as transcriptional activator, SPI1/PU.1, a major player in haematopoiesis whose alterations are associated with haematological malignancies, has the ability to repress transcription. Here, we investigated the mechanisms underlying gene repression in the erythroid lineage, in which SPI1 exerts an oncogenic function by blocking differentiation. We show that SPI1 represses genes by binding active enhancers that are located in intergenic or gene body regions. HDAC1 acts as a cooperative mediator of SPI1-induced transcriptional repression by deacetylating SPI1-bound enhancers in a subset of genes, including those involved in erythroid differentiation. Enhancer deacetylation impacts on promoter acetylation, chromatin accessibility and RNA pol II occupancy. In addition to the activities of HDAC1, polycomb repressive complex 2 (PRC2) reinforces gene repression by depositing H3K27me3 at promoter sequences when SPI1 is located at enhancer sequences. Moreover, our study identified a synergistic relationship between PRC2 and HDAC1 complexes in mediating the transcriptional repression activity of SPI1, ultimately inducing synergistic adverse effects on leukaemic cell survival. Our results highlight the importance of the mechanism underlying transcriptional repression in leukemic cells, involving complex functional connections between SPI1 and the epigenetic regulators PRC2 and HDAC1.
|
Titre |
en
HDAC1 and PRC2 mediate combinatorial control in SPI1/PU.1-dependent gene repression in murine erythroleukaemia
|
Auteur(s) |
Sebastian Gregoricchio
1, 2, 3
, Lélia Polit
4
, Michela Esposito
1, 2
, Jérémy Berthelet
5
, Laure Delestré
1, 2
, Emilie Evanno
6
, M’boyba Diop
1, 2
, Isabelle Gallais
6
, Hanna Aleth
7
, Mathilde Poplineau
8, 9
, Wilbert Zwart
3
, Frank Rosenbauer
7
, Fernando Rodrigues-Lima
5
, Estelle Duprez
8, 9
, Valentina Boeva
4, 10
, Christel Guillouf
1, 2
1
Dynamo -
Dynamique moléculaire de la transformation hématopoïétique
( 1057805 )
- Institut Gustave Roussy, Pavillon de recherche 1, 114 rue Edouard-Vaillant, 94805 Villejuif
- France
2
IGR -
Institut Gustave Roussy
( 156104 )
- 114, rue Édouard-Vaillant 94805 Villejuif Cedex -France
- France
3
NKI -
Netherlands Cancer Institute
( 250522 )
- The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
- Pays-Bas
4
IC UM3 (UMR 8104 / U1016) -
Institut Cochin
( 1004701 )
- 22 rue Méchain, 75014 Paris
- France
5
BFA (UMR_8251 / U1133) -
Unité de Biologie Fonctionnelle et Adaptative
( 1005042 )
- Université Paris Diderot, Bât. Buffon, 4 rue Marie-Andrée Lagroua Weill-Hallé, case postale 7081 , 75205 Paris cedex 13
- France
6
U830 -
Unité de génétique et biologie des cancers
( 1004656 )
- Institut Curie
26, rue d'Ulm section de recherche
75248 Paris cedex 05
- France
7
WWU -
Westfälische Wilhelms-Universität Münster = University of Münster
( 325710 )
- Universität Münster Schlossplatz 2 48149 Münster
- Allemagne
8
CRCM -
Centre de Recherche en Cancérologie de Marseille
( 179570 )
- 27 bd Leï Roure, BP 300059
13273 Marseille Cedex 09
- France
9
IPC -
Institut Paoli-Calmettes
( 301325 )
- 232 Boulevard de Sainte-Marguerite
13009 Marseille
- France
10
D-INFK -
Department of Computer Science [ETH Zürich]
( 83910 )
- Haldeneggsteig 4 / Weinbergstrasse 8092 Zürich
- Suisse
|
Licence |
Paternité - Pas d'utilisation commerciale
|
Page/Identifiant |
7938-7958
|
Langue du document |
Anglais
|
Nom de la revue |
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
Audience |
Internationale
|
Date de publication |
2022-08-12
|
Volume |
50
|
Numéro |
14
|
Projet(s) ANR |
|
Domaine(s) |
|
Mots-clés |
en
Gene Regulation, Chromatin and Epigenetics
|
DOI | 10.1093/nar/gkac613 |
Pubmed Id | 35871293 |
PubMed Central | PMC9371914 |
Origine :
Fichiers éditeurs autorisés sur une archive ouverte
Licence :
Paternité - Pas d'utilisation commerciale
- CC BY 4.0
Licence :
![](/build/img/licences/cc.1ab04b8f.png)
![](/build/img/licences/by.1a6bf697.png)
![](/build/img/licences/nc.10ff91f8.png)
Loading...