Post-translational modifications of histone variant H2A.Z accompany gene transactivation, but its modifying enzymes still remain elusive. Here, we reveal a hitherto unknown function of human KAT2A (GCN5) as a histone acetyltransferase (HAT) of H2A.Z at the promoters of a set of transactivated genes. Expression of these genes also depends on the DNA repair complex XPC–RAD23–CEN2. We established that XPC–RAD23–CEN2 interacts both with H2A.Z and KAT2A to drive the recruitment of the HAT at promoters and license H2A.Z acetylation. KAT2A selectively acetylates H2A.Z.1 versus H2A.Z.2 in vitro on several well-defined lysines and we unveiled that alanine-14 in H2A.Z.2 is responsible for inhibiting the activity of KAT2A. Notably, the use of a nonacetylable H2A.Z.1 mutant shows that H2A.Z.1ac recruits the epigenetic reader BRD2 to promote RNA polymerase II recruitment. Our studies identify KAT2A as an H2A.Z.1 HAT in mammals and implicate XPC–RAD23–CEN2 as a transcriptional co-activator licensing the reshaping of the promoter epigenetic landscape.
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Data are available on SRA repository under accession number PRJNA517640. Further information and requests for resources and reagents should be directed to the lead contact, F.C. (email@example.com).
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We are grateful to A. Hamiche, L. Tora and A. Poterszman (IGBMC, France) for expression vectors and antibodies, to K. Sugasawa (Kobe University, Japan) for the antibodies against CEN2 and to members of our team. We thank L. Tora for critical reading and IGBMC antibody and cell culture facilities. This study was supported by the INCA (2017-11537), the ligue contre le cancer (Equipe labélisée 2019, FC) and the ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame program Investissements d’Avenir ANR-10-IDEX-0002-02. M.S was supported by ‘le prix d’encouragement à la recherche de la province Sud (New Caledonia)’. G.C. was supported by a PhD fellowship (2214-A) from the Scientific and Technological Research Council of Turkey (TÜBİTAK). Sequencing was performed by the IGBMC Microarray and Sequencing platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009). Note that part of the text in this article may overlap with the published thesis by M. Semer.
The authors declare no competing interests.
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