The solution structure of the first PHD finger of autoimmune regulator in complex with non-modified histone H3 tail reveals the antagonistic role of H3R2 methylation.
Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus.
Chignola
Francesca
F
Biomolecular NMR Laboratory, Dulbecco Telethon Institute, Milan, Italy.
Gaetani
Massimiliano
M
Rebane
Ana
A
Org
Tõnis
T
Mollica
Luca
L
Zucchelli
Chiara
C
Spitaleri
Andrea
A
Mannella
Valeria
V
Peterson
Pärt
P
Musco
Giovanna
G
D002460:Cell Line; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017354:Point Mutation; D012996:Solutions; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015533:Transcriptional Activation; D016335:Zinc Fingers; D000096927:AIRE Protein
D006657:Histones; D012996:Solutions; D014157:Transcription Factors; D000096927:AIRE Protein