Molecular Cell
Volume 38, Issue 2, 23 April 2010, Pages 165-178
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Article
A Functional Link between the Histone Demethylase PHF8 and the Transcription Factor ZNF711 in X-Linked Mental Retardation

https://doi.org/10.1016/j.molcel.2010.03.002Get rights and content
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Summary

X-linked mental retardation (XLMR) is an inherited disorder that mostly affects males and is caused by mutations in genes located on the X chromosome. Here, we show that the XLMR protein PHF8 and a C. elegans homolog F29B9.2 catalyze demethylation of di- and monomethylated lysine 9 of histone H3 (H3K9me2/me1). The PHD domain of PHF8 binds to H3K4me3 and colocalizes with H3K4me3 at transcription initiation sites. Furthermore, PHF8 interacts with another XMLR protein, ZNF711, which binds to a subset of PHF8 target genes, including the XLMR gene JARID1C. Of interest, the C. elegans PHF8 homolog is highly expressed in neurons, and mutant animals show impaired locomotion. Taken together, our results functionally link the XLMR gene PHF8 to two other XLMR genes, ZNF711 and JARID1C, indicating that MR genes may be functionally linked in pathways, causing the complex phenotypes observed in patients developing MR.

Highlights

► PHF8 H3K9me2/me1 demethylase activity is lost in XLMR-associated PHF8 mutants ► PHF8 binds to most promoters with H3K4Me3, likely through its PHD finger ► The XLMR protein ZNF711 binds PHF8 and recruits PHF8 to many of its targets ► F29B9.2, a C. elegans PHF8 homolog, demethylates both H3K9me2 and H3K27me2

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These authors contributed equally to this work