A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, coactivates nuclear receptors, and counteracts heterochromatin silencing.
Transcriptional activators, several different coactivators, and general transcription factors are necessary to access specific loci in the dense chromatin structure to allow precise initiation of RNA polymerase II (Pol II) transcription. Histone acetyltransferase (HAT) complexes were implicated in loosening the chromatin around promoters and thus in gene activation. Here we demonstrate that the 2 MDa GCN5 HAT-containing metazoan TFTC/STAGA complexes contain a histone H2A and H2B deubiquitinase activity. We have identified three additional subunits of TFTC/STAGA (ATXN7L3, USP22, and ENY2) that form the deubiquitination module. Importantly, we found that this module is an enhancer of position effect variegation in Drosophila. Furthermore, we demonstrate that ATXN7L3, USP22, and ENY2 are required as cofactors for the full transcriptional activity by nuclear receptors. Thus, the deubiquitinase activity of the TFTC/STAGA HAT complex is necessary to counteract heterochromatin silencing and acts as a positive cofactor for activation by nuclear receptors in vivo.
Zhao
Yue
Y
Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
Lang
Guillaume
G
Ito
Saya
S
Bonnet
Jacques
J
Metzger
Eric
E
Sawatsubashi
Shun
S
Suzuki
Eriko
E
Le Guezennec
Xavier
X
Stunnenberg
Hendrik G
HG
Krasnov
Aleksey
A
Georgieva
Sofia G
SG
Schüle
Roland
R
Takeyama
Ken-Ichi
K
Kato
Shigeaki
S
Tora
László
L
Devys
Didier
D
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D020868:Gene Silencing; D006570:Heterochromatin / Q000235:genetics*; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D025941:Protein Interaction Mapping; D012319:RNA Polymerase II / Q000502:physiology; D011944:Receptors, Androgen / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000502:physiology; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D035165:Transcription Factors, General / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics*; D043222:Ubiquitin Thiolesterase; D054875:Ubiquitination / Q000502:physiology*; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000502:physiology; D000099224:p300-CBP-Associated Factor
D029721:Drosophila Proteins; D010450:Endopeptidases; D006570:Heterochromatin; D051548:Histone Acetyltransferases; D046912:Multiprotein Complexes; D012319:RNA Polymerase II; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D013869:Thiolester Hydrolases; D015534:Trans-Activators; D014157:Transcription Factors; D035165:Transcription Factors, General; D043222:Ubiquitin Thiolesterase; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C527169:ATXN7L3 protein, human; C527171:Eny2 protein, human; C527172:Sgf11 protein, Drosophila; C423782:e(y)2 protein, Drosophila; C421164:not protein, Drosophila; C527170:Usp22 protein, human