title: MRG15 is required for pre-mRNA splicing and spermatogenesis.
abstract: Splicing can be epigenetically regulated and involved in cellular differentiation in somatic cells, but the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. To study these interactions in vivo, we generated a germline deletion of MORF-related gene on chromosome 15 (MRG15), a multifunctional chromatin organizer that binds to methylated histone H3 lysine 36 (H3K36) in introns of transcriptionally active genes and has been implicated in regulation of histone acetylation, homology-directed DNA repair, and alternative splicing in somatic cells. Conditional KO (cKO) males lacking MRG15 in the germline are sterile secondary to spermatogenic arrest at the round spermatid stage. There were no significant alterations in meiotic division and histone acetylation. Specific mRNA sequences disappeared from 66 germ cell-expressed genes in the absence of MRG15, and specific intronic sequences were retained in mRNAs of 4 genes in the MRG15 cKO testes. In particular, introns were retained in mRNAs encoding the transition proteins that replace histones during sperm chromatin condensation. In round spermatids, MRG15 colocalizes with splicing factors PTBP1 and PTBP2 at H3K36me3 sites between the exons and single intron of transition nuclear protein 2 (Tnp2). Thus, our results reveal that MRG15 is essential for pre-mRNA splicing during spermatogenesis and that epigenetic regulation of pre-mRNA splicing by histone modification could be useful to understand not only spermatogenesis but also, epigenetic disorders underlying male infertile patients.
authors: Laboratory of Biomedicine, Division of Pathobiology, Department of Basic Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan; Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030; iwamori@anim.med.kyushu-u.ac.jp mmatzuk@bcm.edu.
authors: Naoki
authors: N
authors: Iwamori
authors: Division of Functional Biochemistry, Department of Biochemistry, Jichi Medical University, Tochigi 329-0498, Japan;
authors: Kaoru
authors: K
authors: Tominaga
authors: Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors: Tetsuya
authors: T
authors: Sato
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Bioinformatics Research Laboratory, Baylor College of Medicine, Houston, TX 77030;
authors: Kevin
authors: K
authors: Riehle
authors: Laboratory of Biomedicine, Division of Pathobiology, Department of Basic Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan; Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
authors: Tokuko
authors: T
authors: Iwamori
authors: Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors: Yasuyuki
authors: Y
authors: Ohkawa
authors: Bioinformatics Research Laboratory, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030;
authors: Cristian
authors: C
authors: Coarfa
authors: Laboratory of Biomedicine, Division of Pathobiology, Department of Basic Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan; Center of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;
authors: Etsuro
authors: E
authors: Ono
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030 iwamori@anim.med.kyushu-u.ac.jp mmatzuk@bcm.edu.
authors: Martin M
authors: MM
authors: Matzuk
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D005854:Germ Cells / Q000254:growth & development / Q000473:pathology; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013091:Spermatogenesis / Q000235:genetics*; D013737:Testis / Q000254:growth & development / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C471162:MRG15 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C573992:Ptbp1 protein, mouse; C429773:Ptbp2 protein, mouse; C489505:Tnp2 protein, mouse; D015534:Trans-Activators; D038941:Polypyrimidine Tract-Binding Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: epigenetics; fertility defects; infertility; spermiogenesis; splicing defects