title: Methylation of histone H4 at aspartate 24 by protein L-isoaspartate O-methyltransferase (PCMT1) links histone modifications with protein homeostasis.
abstract: Histone modifications play crucial roles in modulating chromatin function and transcriptional activity. Due to their long half-life, histones can, in addition to post-translational modifications, also accumulate spontaneous chemical alterations, which can affect their functionality and require either protein repair or degradation. One of the major sources of such protein damage or ageing is the conversion of aspartate into isoaspartate residues that can then be methylated. Here, we characterize a novel histone modification, the methylation of histone H4 at aspartate 24 (H4D24me). We generated H4D24me specific antibodies and showed that H4D24me is ubiquitously present in different mouse and human cells. Our in vitro and in vivo data identified PCMT1 (Protein L-isoaspartate O-methyltransferase), an enzyme involved in protein repair, as a novel H4D24 specific histone methyltransferase. Furthermore, we demonstrated that VprBP (HIV-1 viral protein R (Vpr)-binding protein), a chromo domain-containing protein, specifically recognizes H4D24me potentially implicating H4D24me in H4 degradation. Thus, this work links for the first time a histone modification with histone protein aging and histone homeostasis, suggesting novel functions for histone modifications beyond transcriptional regulation.
authors.affiliation: 1] Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 67404 Illkirch, France [2] Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg im Breisgau, Germany [3] University of Freiburg, Fahnenbergplatz, 79085 Freiburg im Breisgau, Germany.
authors.forename: Burcu
authors.initials: B
authors.lastname: Biterge
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg im Breisgau, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Richter
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg im Breisgau, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mittler
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008745:Methylation; D051379:Mice; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics
chemical_list: D000906:Antibodies; D006657:Histones; D001224:Aspartic Acid; C435725:PCMT1 protein, human; D026601:Protein D-Aspartate-L-Isoaspartate Methyltransferase