title: The Histone Demethylase KDM5 Activates Gene Expression by Recognizing Chromatin Context through Its PHD Reader Motif.
abstract: KDM5 family proteins are critically important transcriptional regulators whose physiological functions in the context of a whole animal remain largely unknown. Using genome-wide gene expression and binding analyses in Drosophila adults, we demonstrate that KDM5 (Lid) is a direct regulator of genes required for mitochondrial structure and function. Significantly, this occurs independently of KDM5's well-described JmjC domain-encoded histone demethylase activity. Instead, it requires the PHD motif of KDM5 that binds to histone H3 that is di- or trimethylated on lysine 4 (H3K4me2/3). Genome-wide, KDM5 binding overlaps with the active chromatin mark H3K4me3, and a fly strain specifically lacking H3K4me2/3 binding shows defective KDM5 promoter recruitment and gene activation. KDM5 therefore plays a central role in regulating mitochondrial function by utilizing its ability to recognize specific chromatin contexts. Importantly, KDM5-mediated regulation of mitochondrial activity is likely to be key in human diseases caused by dysfunction of this family of proteins.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Xingyin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: julie.secombe@einstein.yu.edu.
authors.forename: Julie
authors.initials: J
authors.lastname: Secombe
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002843:Chromatin; D047369:Chromatin Immunoprecipitation; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D056466:Histone Demethylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002843:Chromatin; D029721:Drosophila Proteins; D006657:Histones; D056466:Histone Demethylases; C518655:Lid protein, Drosophila
keywords: H3K4me3; KDM5; Lid; PHD motif; histone; mitochondria; transcription