title: PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression.
abstract: Histone methylation occurs on both lysine and arginine residues, and its dynamic regulation plays a critical role in chromatin biology. Here we identify the UHRF1 PHD finger (PHD(UHRF1)), an important regulator of DNA CpG methylation, as a histone H3 unmodified arginine 2 (H3R2) recognition modality. This conclusion is based on binding studies and cocrystal structures of PHD(UHRF1) bound to histone H3 peptides, where the guanidinium group of unmodified R2 forms an extensive intermolecular hydrogen bond network, with methylation of H3R2, but not H3K4 or H3K9, disrupting complex formation. We have identified direct target genes of UHRF1 from microarray and ChIP studies. Importantly, we show that UHRF1's ability to repress its direct target gene expression is dependent on PHD(UHRF1) binding to unmodified H3R2, thereby demonstrating the functional importance of this recognition event and supporting the potential for crosstalk between histone arginine methylation and UHRF1 function.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eerappa
authors.initials: E
authors.lastname: Rajakumara
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Zhentian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Honghui
authors.initials: H
authors.lastname: Ma
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Hu
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Feizhen
authors.initials: F
authors.lastname: Wu
authors.affiliation: Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.affiliation: Constellation Pharmaceuticals, Cambridge, MA 02140, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Lan
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.|Endocrinology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yujiang Geno
authors.initials: YG
authors.lastname: Shi
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.|State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
authors.affiliation: Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.|Department of Biochemistry, Fudan University Medical School, Shanghai 200032, China.|Division of Newborn Medicine and Program in Epigenetics, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D022041:Euchromatin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D045325:HCT116 Cells; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D022041:Euchromatin; D006657:Histones; D014157:Transcription Factors; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases