title: Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation.
abstract: A fundamental challenge in mammalian biology has been the elucidation of mechanisms linking DNA methylation and histone post-translational modifications. Human UHRF1 (ubiquitin-like PHD and RING finger domain-containing 1) has multiple domains that bind chromatin, and it is implicated genetically in the maintenance of DNA methylation. However, molecular mechanisms underlying DNA methylation regulation by UHRF1 are poorly defined. Here we show that UHRF1 association with methylated histone H3 Lys9 (H3K9) is required for DNA methylation maintenance. We further show that UHRF1 association with H3K9 methylation is insensitive to adjacent H3 S10 phosphorylation--a known mitotic 'phospho-methyl switch'. Notably, we demonstrate that UHRF1 mitotic chromatin association is necessary for DNA methylation maintenance through regulation of the stability of DNA methyltransferase-1. Collectively, our results define a previously unknown link between H3K9 methylation and the faithful epigenetic inheritance of DNA methylation, establishing a notable mitotic role for UHRF1 in this process.
authors.affiliation: Department of Biochemistry & Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Krajewski
authors.forename: Nataliya
authors.initials: N
authors.lastname: Nady
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: Sheng
authors.initials: S
authors.lastname: Xue
authors.forename: Aimee I
authors.initials: AI
authors.lastname: Badeaux
authors.forename: Dalia
authors.initials: D
authors.lastname: Barsyte-Lovejoy
authors.forename: Jorge Y
authors.initials: JY
authors.lastname: Martinez
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bedford
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Fuchs
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
mesh_terms: D000595:Amino Acid Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism*; D003001:Cloning, Molecular; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic / Q000502:physiology*; D004926:Escherichia coli; D005454:Fluorescence Polarization; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D046228:Microarray Analysis; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002843:Chromatin; D017931:DNA Primers; D006657:Histones; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases