Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells
Yuichi Morozumi
(1)
,
Fayçal Boussouar
(1)
,
Minjia Tan
(2)
,
Apirat Chaikuad
(3, 4)
,
Mahya Jamshidikia
(1)
,
Gozde Colak
(5)
,
Huang He
(5)
,
Litong Nie
(2)
,
Carlo Petosa
(6)
,
Maud de Dieuleveult
(7)
,
Sandrine Curtet
(1)
,
Anne-Laure Vitte
(1)
,
Clothilde Rabatel
(1)
,
Alexandra Debernardi
(1)
,
Cosset François-Loïc
(8)
,
Els Verhoeyen
(8, 9)
,
Anouk Emadali
(1)
,
Norbert Schweifer
(10)
,
Davide Gianni
(10)
,
Marta Gut
(11)
,
Philippe Guardiola
(12)
,
Sophie Rousseaux
(1)
,
Matthieu Gérard
(7)
,
Stefan Knapp
(3, 4)
,
Yingming Zhao
(2, 5)
,
Saadi Khochbin
(1)
1
INSERM U823 -
Institut d'oncologie/développement Albert Bonniot de Grenoble
2 The Chemical Proteomics Center and State Key Laboratory of Drug Research
3 Structural Genomics Consortium
4 Nuffield Department of Clinical Medicine [Oxford]
5 Ben May Department of Cancer Research
6 IBS - UMR 5075 - Institut de biologie structurale
7 I2BC - Institut de Biologie Intégrative de la Cellule
8 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
9 INSERM U1065 - C3M - Equipe “Contrôle Métabolique des Morts Cellulaires”
10 Boehringer Ingelheim RCV
11 CRG - Centre for Genomic Regulation [Barcelona]
12 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
2 The Chemical Proteomics Center and State Key Laboratory of Drug Research
3 Structural Genomics Consortium
4 Nuffield Department of Clinical Medicine [Oxford]
5 Ben May Department of Cancer Research
6 IBS - UMR 5075 - Institut de biologie structurale
7 I2BC - Institut de Biologie Intégrative de la Cellule
8 EVIR - Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy
9 INSERM U1065 - C3M - Equipe “Contrôle Métabolique des Morts Cellulaires”
10 Boehringer Ingelheim RCV
11 CRG - Centre for Genomic Regulation [Barcelona]
12 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
Fayçal Boussouar
- Function : Author
- PersonId : 775803
- ORCID : 0000-0003-4529-4893
Mahya Jamshidikia
- Function : Author
- PersonId : 775804
- ORCID : 0000-0003-4460-292X
Carlo Petosa
- Function : Author
- PersonId : 742156
- IdHAL : carlo-petosa
- ORCID : 0000-0002-9975-1167
- IdRef : 158806298
Maud de Dieuleveult
- Function : Author
- PersonId : 763676
- ORCID : 0000-0002-3387-1836
Cosset François-Loïc
- Function : Author
- PersonId : 746240
- IdHAL : francois-loic-cosset
- ORCID : 0000-0001-8842-3726
- IdRef : 11115104X
Marta Gut
- Function : Author
- PersonId : 764586
- ORCID : 0000-0002-4063-7159
Sophie Rousseaux
- Function : Author
- PersonId : 758736
- ORCID : 0000-0001-5246-5350
- IdRef : 080608078
Abstract
Although the conserved AAA ATPase and bromodomain factor, ATAD2, has been described as a transcriptional co-activator upregulated in many cancers, its function remains poorly understood. Here, using a combination of ChIP-seq, ChIP-proteomics, and RNA-seq experiments in embryonic stem cells where Atad2 is normally highly expressed, we found that Atad2 is an abundant nucleosome-bound protein present on active genes, associated with chromatin remodelling, DNA replication, and DNA repair factors. A structural analysis of its bromodomain and subsequent investigations demonstrate that histone acetylation guides ATAD2 to chromatin, resulting in an overall increase of chromatin accessibility and histone dynamics, which is required for the proper activity of the highly expressed gene fraction of the genome. While in exponentially growing cells Atad2 appears dispensable for cell growth, in differentiating ES cells Atad2 becomes critical in sustaining specific gene expression programmes, controlling proliferation and differentiation. Altogether, this work defines Atad2 as a facilitator of general chromatin-templated activities such as transcription.