title: Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein.
abstract: Histone modifications and DNA methylation represent two layers of heritable epigenetic information that regulate eukaryotic chromatin structure and gene activity. UHRF1 is a unique factor that bridges these two layers; it is required for maintenance DNA methylation at hemimethylated CpG sites, which are specifically recognized through its SRA domain and also interacts with histone H3 trimethylated on lysine 9 (H3K9me3) in an unspecified manner. Here we show that UHRF1 contains a tandem Tudor domain (TTD) that recognizes H3 tail peptides with the heterochromatin-associated modification state of trimethylated lysine 9 and unmodified lysine 4 (H3K4me0/K9me3). Solution NMR and crystallographic data reveal the TTD simultaneously recognizes H3K9me3 through a conserved aromatic cage in the first Tudor subdomain and unmodified H3K4 within a groove between the tandem subdomains. The subdomains undergo a conformational adjustment upon peptide binding, distinct from previously reported mechanisms for dual histone mark recognition. Mutant UHRF1 protein deficient for H3K4me0/K9me3 binding shows altered localization to heterochromatic chromocenters and fails to reduce expression of a target gene, p16(INK4A), when overexpressed. Our results demonstrate a novel recognition mechanism for the combinatorial readout of histone modification states associated with gene silencing and add to the growing evidence for coordination of, and cross-talk between, the modification states of H3K4 and H3K9 in regulation of gene expression.
authors.affiliation: Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Nady
authors.forename: Alexander
authors.initials: A
authors.lastname: Lemak
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: George V
authors.initials: GV
authors.lastname: Avvakumov
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kareta
authors.forename: Mayada
authors.initials: M
authors.lastname: Achour
authors.forename: Sheng
authors.initials: S
authors.lastname: Xue
authors.forename: Shili
authors.initials: S
authors.lastname: Duan
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zuo
authors.forename: Yun-Xing
authors.initials: YX
authors.lastname: Wang
authors.forename: Christian
authors.initials: C
authors.lastname: Bronner
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chédin
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
mesh_terms: D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands / Q000502:physiology; D018360:Crystallography, X-Ray; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006570:Heterochromatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D019906:Nuclear Magnetic Resonance, Biomolecular; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006570:Heterochromatin; D006657:Histones; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases