Control of histone H3 lysine 9 (H3K9) methylation state via cooperative two-step demethylation by Jumonji domain containing 1A (JMJD1A) homodimer.
Post-translational histone methylation is a dynamic and reversible process that is involved in the spatio-temporal regulation of gene transcription and contributes to various cellular phenotypes. Methylation of histone H3 at lysine 9 (H3K9), which is generally a transcriptional repression mark, is demethylated by H3K9-specific demethylases, leading to transcriptional activation. However, how multiple demethylases with the same substrate specificity differ in their chromatin targeting mechanisms has not been well understood. Unlike other H3K9-specific demethylases, it has been reported that JMJD1A likely forms a homodimer, but a detailed mode of dimerization and the possible link between structure and enzymatic activity have remained unresolved. Here, we report the structure-function relationship of JMJD1A in detail. First, JMJD1A forms a homodimer through its catalytic domains, bringing the two active sites close together. Second, increasing the concentration of JMJD1A facilitates efficient production of unmethylated product from dimethyl-H3K9 and decreases the release of the monomethylated intermediate. Finally, substituting one of the two active sites with an inactive mutant results in a significant reduction of the demethylation rate without changing the affinity to the intermediate. Given this evidence, we propose a substrate channeling model for the efficient conversion of dimethylated H3K9 into the unmethylated state. Our study provides valuable information that will help in understanding the redundancy of H3K9-specific demethylases and the complementary activity of their unique structures and enzymatic properties for appropriate control of chromatin modification patterns.
From the Genome Science Division, Research Center for Advanced Science and Technology, and.
Satoshi
S
Goda
Takayuki
T
Isagawa
Yoko
Y
Chikaoka
Takeshi
T
Kawamura
Hiroyuki
H
Aburatani
D020134:Catalytic Domain; D002460:Cell Line; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D008954:Models, Biological; D009154:Mutation; D055503:Protein Multimerization / Q000502:physiology*; D013329:Structure-Activity Relationship
D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human
Chromatin Biology; Chromatin Histone Modification; Dimerization; Enzyme Mechanisms; Histone Lysine Demethylase; Histone Methylation; JMJD1A; Mass Spectrometry (MS); Surface Plasmon Resonance (SPR)