14-3-3 proteins recognize a histone code at histone H3 and are required for transcriptional activation.
Interphase phosphorylation of S10 at histone H3 is linked to transcriptional activation of a specific subset of mammalian genes like HDAC1. Recently, 14-3-3 proteins have been described as detectors for this phosphorylated histone H3 form. Here, we report that 14-3-3 binding is modulated by combinatorial modifications of histone H3. S10 phosphorylation is necessary for an interaction, but additional H3K9 or H3K14 acetylation increases the affinity of 14-3-3 for histone H3. Histone H3 phosphoacetylation occurs concomitant with K9 methylation in vivo, suggesting that histone phosphorylation and acetylation can synergize to overcome repressive histone methylation. Chromatin immunoprecipitation experiments reveal recruitment of 14-3-3 proteins to the HDAC1 gene in an H3S10ph-dependent manner. Recruitment of 14-3-3 to the promoter is enhanced by additional histone H3 acetylation and correlates with dissociation of the repressive binding module HP1gamma. Finally, siRNA-mediated loss of 14-3-3 proteins abolishes the transcriptional activation of HDAC1. Together our data indicate that 14-3-3 proteins are crucial mediators of histone phosphoacetylation signals.
Max F Perutz Laboratories, Vienna Biocenter, Medical University of Vienna, Vienna, Austria.
Stefan
S
Winter
Elisabeth
E
Simboeck
Wolfgang
W
Fischle
Gordin
G
Zupkovitz
Ilse
I
Dohnal
Karl
K
Mechtler
Gustav
G
Ammerer
Christian
C
Seiser
D048948:14-3-3 Proteins / Q000302:isolation & purification / Q000502:physiology*; D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D006367:HeLa Cells; D042421:Histone Code / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D041701:Swiss 3T3 Cells; D015533:Transcriptional Activation / Q000502:physiology*
D048948:14-3-3 Proteins; D006657:Histones; D010446:Peptide Fragments