Open AccessTranscription factor Ap2δ associates with Ash2l and ALR, a trithorax family histone methyltransferase, to activate Hoxc8 transcription
Author(s) -
Cheryl C. Tan,
K. V. Sindhu,
SiDe Li,
Hisahide Nishio,
Jason Z. Stoller,
Kimihiko Oishi,
Sahitya Puttreddy,
Tamara J. Lee,
Jonathan A. Epstein,
Martin J. Walsh,
Bruce D. Gelb
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0711896105
Subject(s) - biology , histone methyltransferase , transactivation , transcription factor , genetics , enhancer , h3k4me3 , histone , histone h3 , chromatin , methyltransferase , histone methylation , microbiology and biotechnology , promoter , gene , dna methylation , gene expression , methylation
The family of Ap2 transcription factors comprises five members with highly conserved DNA-binding domains. Among the family members, Ap2δ is the most divergent, because it lacks highly conserved residues within the transactivation domain (TAD) and has weak affinity for known Ap2 binding sites. To identify specific Ap2δ coactivators/regulators during development, we performed a yeast two-hybrid screen, using Ap2δ's TAD. We identified the trithorax superfamily member, Ash2l, as a binding partner that interacts exclusively with Ap2δ. We showed that Ash2l positively mediates Ap2δ transactivation in a dose-dependent manner. Given the known role of Ash2l in histone modification, we determined whether Ap2δ was able to form a complex with that activity. Our results showed that Ap2δ associates with endogenous ASH2L and a member of the MLL family of histone lysine methyltransferases (HKMTs), MLL2 (ALR), forming a complex that methylates lysine 4 of histone H3 (H3K4). Additionally, we showed that Ap2δ is necessary for recruitment of Ash2l and Alr to theHoxc8 locus and that recruitment of this complex leads to H3K4 trimethylation (H3K4me3) and subsequent gene activation. Altogether, we provide evidence of an association between a highly restricted gene-specific transcription factor and a Su(var), Enhancer of Zeste, Trithorax (SET)1/trithorax-like complex with H3K4 methyltransferase activity. Our studies also document a functional role for Ap2δ in recruiting histone methyltransferases (HMTs) to specific gene targets, such asHoxc8 . This role provides a mechanism through which these transcription factors can have diverse effects despite nearly identical DNA-binding motifs.