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FEBS J 2021 Mar 25. Epub 2021 Mar 25.

School of Biotechnology and Biomolecular Sciences, University of New South Wales, New South Wales, 2052, Australia.

Protein arginine methyltransferase 6 (PRMT6) catalyses the asymmetric dimethylation of arginines on numerous substrate proteins within the human cell. In particular, PRMT6 methylates histone H3 arginine 2 (H3R2) which affects both gene repression and activation. However, the substrate specificity of PRMT6 has not been comprehensively analysed. Read More

Biochem J 2020 Nov 27. Epub 2020 Nov 27.

University of Texas M.D Anderson Cancer Center, Houston, Texas, United States.

Arginine methylation is a post-translational modification that is implicated in multiple biological functions including transcriptional regulation. The expression of protein arginine methyltransferases (PRMT) has been shown to be upregulated in various cancers. PRMTs have emerged as attractive targets for the development of new cancer therapies. Read More

Biochem Biophys Res Commun 2020 09 29;530(1):75-81. Epub 2020 Jul 29.

College of Life Science and Technology, Jinan University, Guangzhou, 510630, China; Institute of Biomedicine & National Engineering Research Center of Genetic Medicine, Guangzhou, 510630, China. Electronic address:

The protein arginine methyltransferase 6 (PRMT6) is a coregulator of gene expression by methylation of the histone H3 on arginine 2 (H3R2), H4R3 and H2AR3 [1,2]. PRMT6 is aberrantly expressed in various types of human cancer, and abnormal methylation in cancers caused by overexpression of PRMT6 is considered to correlate with poor recovery prognosis [3,4]. However, mechanisms that regulate PRMT6 protein stability in cells remain largely unknown. Read More

Biochemistry 2020 10 31;59(39):3696-3708. Epub 2020 Mar 31.

Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, United States.

Histone H3 arginine 2 (H3R2) is post-translationally modified in three different states by "writers" of the protein arginine methyltransferase (PRMT) family. H3R2 methylarginine isoforms include PRMT5-catalyzed monomethylation (me1) and symmetric dimethylation (me2s) and PRMT6-catalyzed me1 and asymmetric dimethylation (me2a). WD-40 repeat-containing protein 5 (WDR5) is an epigenetic "reader" protein that interacts with H3R2. Read More

Redox Biol 2020 01 12;28:101322. Epub 2019 Sep 12.

Centers for Metabolic Disease Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. Electronic address:

Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease. We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. Read More

Biochem J 2019 07 15;476(13):1957-1973. Epub 2019 Jul 15.

Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China

Spp1, a plant homeodomain (PHD) finger containing protein, is a critical subunit of the histone H3K4 methyltransferase complex of proteins associated with Set1 (COMPASS). The chromatin binding affinity of the PHD finger of Spp1 has been proposed to modulate COMPASS activity. During meiosis, Spp1 plays another role in promoting programmed double-strand break (DSB) formation by binding H3K4me3 via its PHD finger and interacting with a DSB protein, Mer2. Read More

Gastroenterology 2019 09 30;157(3):744-759.e4. Epub 2019 May 30.

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Background & Aims: Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis. Read More

Carcinogenesis 2019 03;40(1):15-26

Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Histone modification plays important molecular roles in development and progression of cancers. Dysregulation of histone H3 arginine (R) methylation is still unknown in primary cancer, including gastric cancer (GC). Although PRMT6 contributes to asymmetric dimethylation at H3R2 (H3R2me2as) in cancer cells, its molecular functions are poorly understood in GC. Read More

Cell Rep 2018 09;24(12):3339-3352

Institute for Molecular Biology and Tumor Research (IMT), Philipps-University Marburg, Hans-Meerwein-Strasse 2, BMFZ, 35043 Marburg, Germany. Electronic address:

Protein arginine methyltransferase 6 (PRMT6) catalyzes asymmetric dimethylation of histone H3 at arginine 2 (H3R2me2a). This mark has been reported to associate with silent genes. Here, we use a cell model of neural differentiation, which upon PRMT6 knockout exhibits proliferation and differentiation defects. Read More

Bone 2018 12 3;117:37-46. Epub 2018 Sep 3.

Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, USA.

Protein arginine methyltransferases (PRMTs) catalyze symmetric and asymmetric methylation on arginine residues of multiple protein targets including histones and have essential roles in organismal development and disease. PRMT5 mediates symmetric di-methylation (sDMA) of arginine 2 (H3R2me2s) and arginine 8 on histone 3 (H3R8me2s), arginine 3 on histones 2A and 4 (H2A/H4R3me2s) as well as several non-histone substrates like Sm proteins. Here, we found that selective inhibition of PRMT5 in mesenchymal stromal cells (MSCs) led to a reduction in colony forming units (CFUs) and increased osteoblast differentiation. Read More

Plant Cell 2018 01 12;30(1):167-177. Epub 2017 Dec 12.

National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Center for Plant Stress Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201602, China

In chromatin, histone methylation affects the epigenetic regulation of multiple processes in animals and plants and is modulated by the activities of histone methyltransferases and histone demethylases. The jumonji domain-containing histone demethylases have diverse functions and can be classified into several subfamilies. In humans, the jumonji domain-containing Lysine (K)-Specific Demethylase 5/Jumonji and ARID Domain Protein (KDM5/JARID) subfamily demethylases are specific for histone 3 lysine 4 trimethylation (H3K4me3) and are important drug targets for cancer treatment. Read More

Anal Chem 2016 09 8;88(17):8441-9. Epub 2016 Aug 8.

School of Pharmacy, Nanjing Medical University , 818 Tian Yuan East Road, Nanjing, 211166, China.

Protein arginine methylation is one of the common post-translational modifications in cellular processes. To date, two isomeric forms of dimethylated arginine have been identified: asymmetric N(G),N(G)-dimethylarginine (aDMA), and symmetric N(G),N'(G)-dimethylarginine (sDMA). Evidence indicated that these isomers can coexist and have different or even opposite functions, with aDMA and sDMA forms of arginine 2 on histone H3 (i. Read More

Biochem J 2016 10 1;473(19):3049-63. Epub 2016 Aug 1.

Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5J 1L7, Canada Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Read More

Nat Commun 2016 Apr 5;7:11197. Epub 2016 Apr 5.

Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China.

UHRF1 is an important epigenetic regulator for maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA (hm-DNA) and trimethylation of histone H3K9 (H3K9me3), but the regulatory mechanism remains unknown. Here we show that UHRF1 adopts a closed conformation, in which a C-terminal region (Spacer) binds to the tandem Tudor domain (TTD) and inhibits H3K9me3 recognition, whereas the SET-and-RING-associated (SRA) domain binds to the plant homeodomain (PHD) and inhibits H3R2 recognition. Read More

Proc Natl Acad Sci U S A 2015 Sep 14;112(39):12139-44. Epub 2015 Sep 14.

Department of Biological Sciences, State University of New York at Buffalo, Buffalo, NY 14260;

Point centromeres are specified by a short consensus sequence that seeds kinetochore formation, whereas regional centromeres lack a conserved sequence and instead are epigenetically inherited. Regional centromeres are generally flanked by heterochromatin that ensures high levels of cohesin and promotes faithful chromosome segregation. However, it is not known whether regional centromeres require pericentromeric heterochromatin. Read More

Biochemistry 2015 Sep 9;54(37):5766-80. Epub 2015 Sep 9.

Department of Chemistry & Biochemistry, South Dakota State University , Box-2202, SAV367, Brookings, South Dakota 57007, United States.

A detailed understanding of the energetic contributions to histone peptide recognition would be valuable for a better understanding of chromatin anchoring mechanisms and histone diagnostic design. Here, we probed the energetic contributions to recognize the same unmodified histone H3 by three different plant homeodomain (PHD) H3K4me0 readers: hKDM5B-PHD1 (first PHD finger of hKDM5B), hBAZ2A-PHD, and hAIRE-PHD1. The energetic contributions of residues differ significantly from one complex to the next. Read More

Mol Genet Genomics 2016 Feb 8;291(1):33-49. Epub 2015 Jul 8.

College of Bioscience and Biotechnology, International Associated Laboratory of CNRS-FU-HAU On Plant Epigenome Research, Hunan Agricultural University, 410128, Changsha, China.

Histone modification regulates plant development events by epigenetically silencing or activating gene expression, and histone methylation is regulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The JmjC domain proteins, an important KDM family, erase methyl marks (CH3-) from histones and play key roles in maintaining homeostasis of histone methylation in vivo. Here, we analyzed 169 JmjC domain proteins from whole genomes of plants ranging from green alga to higher plants together with 36 from two animals (fruit fly and human). Read More

Cell Res 2015 Aug 12;25(8):911-29. Epub 2015 Jun 12.

1] Department of Biology II, Ludwig Maximilians University Munich, Großhaderner Str. 2, 82152 Planegg-Martinsried, Germany [2] Center for Integrated Protein Science Munich (CIPSM), Via Manara 7, 21052 Busto Arsizio (VA), Italy [3] Nanosystems Initiative Munich (NIM), Via Manara 7, 21052 Busto Arsizio (VA), Italy.

DNMT1 is recruited by PCNA and UHRF1 to maintain DNA methylation after replication. UHRF1 recognizes hemimethylated DNA substrates via the SRA domain, but also repressive H3K9me3 histone marks with its TTD. With systematic mutagenesis and functional assays, we could show that chromatin binding further involved UHRF1 PHD binding to unmodified H3R2. Read More

Biochem J 2015 May;467(3):507-15

*The State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.

Protein arginine methyltransferases (PRMTs) are a family of enzymes that can methylate protein arginine residues. PRMTs' substrates include histones and a variety of non-histone proteins. Previous studies have shown that yeast Hmt1 is a type I PRMT and methylates histone H4 arginine 3 and several mRNA-binding proteins. Read More

Mol Oncol 2014 Mar 30;8(2):389-400. Epub 2013 Dec 30.

The Department of Obstetrics and Gynecology, San Antonio, TX 78229, USA; Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. Electronic address:

Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a proto-oncogene that functions as coactivator of the estrogen receptor and is an independent prognostic predictor of shorter survival of breast cancer patients. The dysregulation of PELP1 in breast cancer has been implicated in oncogenesis, metastasis, and therapy resistance. Although several aspects of PELP1 have been studied, a complete list of PELP1 target genes remains unknown, and the molecular mechanisms of PELP1 mediated oncogenesis remain elusive. Read More

J Biol Chem 2013 Jan 16;288(2):1329-39. Epub 2012 Nov 16.

Cancer Institute, Shanghai Cancer Center, Fudan University, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

UHRF1 is an important epigenetic regulator connecting DNA methylation and histone methylations. UHRF1 is required for maintenance of DNA methylation through recruiting DNMT1 to DNA replication forks. Recent studies have shown that the plant homeodomain (PHD) of UHRF1 recognizes the N terminus of unmodified histone H3, and the interaction is inhibited by methylation of H3R2, whereas the tandem tudor domain (TTD) of UHRF1 recognizes trimethylated histone H3 lysine 9 (H3K9me3). Read More

Nucleic Acids Res 2012 Oct 16;40(19):9513-21. Epub 2012 Aug 16.

Terry Fox Molecular Oncology Group and Bloomfield Center for Research on Aging, Segal Cancer Centre, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Department of Oncology, McGill University, Montréal, Québec, Canada, H3T 1E2.

Arginine methylation of histones is a well-known regulator of gene expression. Protein arginine methyltransferase 6 (PRMT6) has been shown to function as a transcriptional repressor by methylating the histone H3 arginine 2 [H3R2(me2a)] repressive mark; however, few targets are known. To define the physiological role of PRMT6 and to identify its targets, we generated PRMT6(-/-) mouse embryo fibroblasts (MEFs). Read More

Biochemistry 2012 Aug 8;51(33):6534-44. Epub 2012 Aug 8.

Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

The chromodomain, helicase, DNA-binding protein 5 (CHD5) is a chromatin remodeling enzyme which is implicated in tumor suppression. In this study, we demonstrate the ability of the CHD5 PHD fingers to specifically recognize the unmodified N-terminus of histone H3. We use two distinct modified peptide-library platforms (beads and glass slides) to determine the detailed histone binding preferences of PHD(1) and PHD(2) alone and the tandem PHD(1-2) construct. Read More

Cell Rep 2012 Feb;1(2):83-90

Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.

The preferential in vitro interaction of the PHD finger of RAG2, a subunit of the V(D)J recombinase, with histone H3 tails simultaneously trimethylated at lysine 4 and symmetrically dimethylated at arginine 2 (H3R2me2sK4me3) predicted the existence of the previously unknown histone modification H3R2me2s. Here, we report the in vivo identification of H3R2me2s . Consistent with the binding specificity of the RAG2 PHD finger, high levels of H3R2me2sK4me3 are found at antigen receptor gene segments ready for rearrangement. Read More

Stem Cells Dev 2012 Sep 8;21(14):2613-22. Epub 2012 May 8.

Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Histone arginine methylation has emerged as an important histone modification involved in gene regulation. Protein arginine methyltransferase (PRMT) 4 and 5 have been shown to play essential roles in early embryonic development and in embryonic stem (ES) cells. Recently, it has been reported that PRMT6-mediated di-methylation of histone H3 at arginine 2 (H3R2me2) can antagonize tri-methylation of histone H3 at lysine 4 (H3K4me3), which marks active genes. Read More

Nat Struct Mol Biol 2012 Jan 8;19(2):136-44. Epub 2012 Jan 8.

Institute of Molecular and Cell Biology, Singapore.

The asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) acts as a repressive mark that antagonizes trimethylation of H3 lysine 4. Here we report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. Profiling of H3-tail interactors by SILAC MS revealed that H3R2me2s excludes binding of RBBP7, a central component of co-repressor complexes Sin3a, NURD and PRC2. Read More

PLoS One 2011 11;6(11):e27599. Epub 2011 Nov 11.

Institut National de Santé et de Recherche Médicale U964/Centre National de Recherche Scientifique UMR 7104/Université de Strasbourg, Illkirch, France.

The human UHRF1 protein (ubiquitin-like containing PHD and RING finger domains 1) has emerged as a potential cancer target due to its implication in cell cycle regulation, maintenance of DNA methylation after replication and heterochromatin formation. UHRF1 functions as an adaptor protein that binds to histones and recruits histone modifying enzymes, like HDAC1 or G9a, which exert their action on chromatin. In this work, we show the binding specificity of the PHD finger of human UHRF1 (huUHRF1-PHD) towards unmodified histone H3 N-terminal tail using native gel electrophoresis and isothermal titration calorimetry. Read More

Nucleic Acids Res 2012 Feb 3;40(4):1536-49. Epub 2011 Nov 3.

Munich Center of Integrated Protein Science and Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, 80336 Munich, Germany.

Histone post-translational modifications play an important role in regulating chromatin structure and gene expression in vivo. Extensive studies investigated the post-translational modifications of the core histones H3 and H4 or the linker histone H1. Much less is known on the regulation of H2A and H2B modifications. Read More

Mol Cell 2011 Jul;43(2):275-284

Laboratory of Epigenetics, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.

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. Read More

PLoS One 2011 Apr 29;6(4):e19442. Epub 2011 Apr 29.

Laboratory of Gene Regulation, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.

Background: The control of gene expression is essential for growth and responses to environmental changes in various organisms. It is known that some meiosis-specific genes are silenced during mitosis and expressed upon nitrogen starvation in Schizosaccharomyces pombe. When the factors responsible for this regulation were studied, a hip3 mutant was isolated via discovery of a defect in the transcriptional repression of meiosis-specific genes. Read More