title: Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals.
abstract: In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated an Uhrf1 knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygous Uhrf1 KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences. In vitro UHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications. We also show that the nucleosome positioning affects the binding of methylated DNA by UHRF1. Thus, while our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Duan
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jiwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Qihan
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.affiliation: Department of Biochemistry and Molecular Biology, Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity, Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.|Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wong
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D022762:CCAAT-Enhancer-Binding Proteins; D018899:CpG Islands / Q000235:genetics*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D004247:DNA; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse; D008239:Lysine