{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T21:50:47Z","timestamp":1790545847994,"version":"4.1.0"},"reference-count":42,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T00:00:00Z","timestamp":1682899200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institute of Child Health and Human Development","award":["HD069592"],"award-info":[{"award-number":["HD069592"]}]},{"name":"National Institute of Child Health and Human Development","award":["HD068157"],"award-info":[{"award-number":["HD068157"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32270905"],"award-info":[{"award-number":["32270905"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Histone modifications regulate chromatin remodeling and gene expression in development and diseases. DOT1L, the sole histone H3K79 methyltransferase, is essential for embryonic development. Here, we report that DOT1L regulates male fertility in mouse. DOT1L associates with MLLT10 in testis. DOT1L and MLLT10 localize to the sex chromatin in meiotic and post-meiotic germ cells in an inter-dependent manner. Loss of either DOT1L or MLLT10 leads to reduced testis weight, decreased sperm count and male subfertility. H3K79me2 is abundant in elongating spermatids, which undergo the dramatic histone-to-protamine transition. Both DOT1L and MLLT10 are essential for H3K79me2 modification in germ cells. Strikingly, histones are substantially retained in epididymal sperm from either DOT1L- or MLLT10-deficient mice. These results demonstrate that H3K79 methylation promotes histone replacement during spermiogenesis.<\/jats:p>","DOI":"10.1242\/dev.201501","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T09:00:17Z","timestamp":1682067617000},"source":"Crossref","is-referenced-by-count":11,"title":["The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis"],"prefix":"10.1242","volume":"150","author":[{"given":"Huijuan","family":"Lin","sequence":"first","affiliation":[{"name":"University of Pennsylvania School of Veterinary Medicine 1 Department of Biomedical Sciences , , Philadelphia, PA 19104 , USA"},{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease, Department of Histoembryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University 2 , Wuhan 430072 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella G.","family":"Cossu","sequence":"additional","affiliation":[{"name":"University of Pennsylvania School of Veterinary Medicine 1 Department of Biomedical Sciences , , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Adrian","family":"Leu","sequence":"additional","affiliation":[{"name":"University of Pennsylvania School of Veterinary Medicine 1 Department of Biomedical Sciences , , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniruddha J.","family":"Deshpande","sequence":"additional","affiliation":[{"name":"Tumor Initiation & Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute 3 , La Jolla, CA 92037 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin M.","family":"Bernt","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia 4 Division of Pediatric Oncology , , Philadelphia, PA 19104 , USA"},{"name":"Perelman School of Medicine, University of Pennsylvania and Abramson Cancer Center 5 Department of Pediatrics , , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7058-5911","authenticated-orcid":false,"given":"Mengcheng","family":"Luo","sequence":"additional","affiliation":[{"name":"Hubei Provincial Key Laboratory of Developmentally Originated Disease, Department of Histoembryology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University 2 , Wuhan 430072 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2311-4089","authenticated-orcid":false,"given":"P. Jeremy","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Pennsylvania School of Veterinary Medicine 1 Department of Biomedical Sciences , , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"2024061306360265700_DEV201501C1","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1093\/biolre\/ioab132","article-title":"RNF8 is not required for histone-to-protamine exchange in spermiogenesisdagger","volume":"105","author":"Abe","year":"2021","journal-title":"Biol. Reprod."},{"key":"2024061306360265700_DEV201501C2","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.ccr.2011.06.010","article-title":"MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L","volume":"20","author":"Bernt","year":"2011","journal-title":"Cancer Cell"},{"key":"2024061306360265700_DEV201501C3","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1128\/MCB.01328-14","article-title":"Characterization of BRD4 during mammalian postmeiotic sperm development","volume":"35","author":"Bryant","year":"2015","journal-title":"Mol. Cell. Biol."},{"key":"2024061306360265700_DEV201501C4","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.ccell.2014.10.009","article-title":"AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes","volume":"26","author":"Deshpande","year":"2014","journal-title":"Cancer Cell"},{"key":"2024061306360265700_DEV201501C5","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1016\/S0960-9822(02)00901-6","article-title":"Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain","volume":"12","author":"Feng","year":"2002","journal-title":"Curr. Biol."},{"key":"2024061306360265700_DEV201501C6","doi-asserted-by":"publisher","first-page":"4483","DOI":"10.1182\/blood-2010-03-276501","article-title":"Early mammalian erythropoiesis requires the Dot1L methyltransferase","volume":"116","author":"Feng","year":"2010","journal-title":"Blood"},{"key":"2024061306360265700_DEV201501C7","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1002\/dvg.20310","article-title":"Generation of a germ cell-specific mouse transgenic Cre line, Vasa-Cre","volume":"45","author":"Gallardo","year":"2007","journal-title":"Genesis"},{"key":"2024061306360265700_DEV201501C8","doi-asserted-by":"publisher","first-page":"3809","DOI":"10.1038\/emboj.2012.233","article-title":"Bromodomain-dependent stage-specific male genome programming by Brdt","volume":"31","author":"Gaucher","year":"2012","journal-title":"EMBO J."},{"key":"2024061306360265700_DEV201501C9","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1016\/j.devcel.2015.01.014","article-title":"SCML2 establishes the male germline epigenome through regulation of histone H2A ubiquitination","volume":"32","author":"Hasegawa","year":"2015","journal-title":"Dev. Cell"},{"key":"2024061306360265700_DEV201501C10","doi-asserted-by":"publisher","first-page":"e1000190","DOI":"10.1371\/journal.pgen.1000190","article-title":"The histone H3K79 methyltransferase Dot1L is essential for mammalian development and heterochromatin structure","volume":"4","author":"Jones","year":"2008","journal-title":"PLoS Genet."},{"key":"2024061306360265700_DEV201501C11","doi-asserted-by":"publisher","first-page":"39698","DOI":"10.1074\/jbc.M112.384057","article-title":"Human histone H3K79 methyltransferase DOT1L protein [corrected] binds actively transcribing RNA polymerase II to regulate gene expression","volume":"287","author":"Kim","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2024061306360265700_DEV201501C12","doi-asserted-by":"publisher","first-page":"30421","DOI":"10.1074\/jbc.C200366200","article-title":"Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase","volume":"277","author":"Lacoste","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2024061306360265700_DEV201501C13","doi-asserted-by":"publisher","first-page":"e1009171","DOI":"10.1371\/journal.pgen.1009171","article-title":"DOT-1.1-dependent H3K79 methylation promotes normal meiotic progression and meiotic checkpoint function in C. elegans","volume":"16","author":"Lascarez-Lagunas","year":"2020","journal-title":"PLoS Genet."},{"key":"2024061306360265700_DEV201501C14","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1038\/ncomms4812","article-title":"Chd5 orchestrates chromatin remodelling during sperm development","volume":"5","author":"Li","year":"2014","journal-title":"Nat. Commun."},{"key":"2024061306360265700_DEV201501C15","doi-asserted-by":"publisher","first-page":"20636","DOI":"10.1038\/s41598-020-77545-6","article-title":"Maternal DOT1L is dispensable for mouse development","volume":"10","author":"Liao","year":"2020","journal-title":"Sci. Rep."},{"key":"2024061306360265700_DEV201501C16","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/cr.2017.117","article-title":"Mettl3-\/Mettl14-mediated mRNA N(6)-methyladenosine modulates murine spermatogenesis","volume":"27","author":"Lin","year":"2017","journal-title":"Cell Res."},{"key":"2024061306360265700_DEV201501C17","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1101\/gad.349550.122","article-title":"Histone methyltransferase DOT1L is essential for self-renewal of germline stem cells","volume":"36","author":"Lin","year":"2022","journal-title":"Genes Dev."},{"key":"2024061306360265700_DEV201501C18","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1016\/j.devcel.2010.01.010","article-title":"RNF8-dependent histone modifications regulate nucleosome removal during spermatogenesis","volume":"18","author":"Lu","year":"2010","journal-title":"Dev. Cell"},{"key":"2024061306360265700_DEV201501C19","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.devcel.2019.10.024","article-title":"Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis","volume":"51","author":"Luense","year":"2019","journal-title":"Dev. Cell"},{"key":"2024061306360265700_DEV201501C20","doi-asserted-by":"publisher","first-page":"e1004954","DOI":"10.1371\/journal.pgen.1004954","article-title":"Polycomb protein SCML2 associates with USP7 and counteracts histone H2A ubiquitination in the XY chromatin during male meiosis","volume":"11","author":"Luo","year":"2015","journal-title":"PLoS Genet."},{"key":"2024061306360265700_DEV201501C21","doi-asserted-by":"publisher","DOI":"10.1101\/2021.10.21.465349","article-title":"DOT1L bridges transcription and heterochromatin formation at pericentromeres","author":"Malla","year":"2021","journal-title":"bioRxiv"},{"key":"2024061306360265700_DEV201501C22","doi-asserted-by":"publisher","first-page":"dev201497","DOI":"10.1242\/dev.201497","article-title":"DOT1L promotes spermatid differentiation by regulating expression of genes required for histone-to-protamine replacement","volume":"150","author":"Malla","year":"2023","journal-title":"Development"},{"key":"2024061306360265700_DEV201501C23","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/nature06906","article-title":"Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation","volume":"453","author":"Mcginty","year":"2008","journal-title":"Nature"},{"key":"2024061306360265700_DEV201501C24","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1002\/mrd.1080310303","article-title":"Highly acetylated H4 is associated with histone displacement in rat spermatids","volume":"31","author":"Meistrich","year":"1992","journal-title":"Mol. Reprod. Dev."},{"key":"2024061306360265700_DEV201501C25","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/j.cub.2006.01.066","article-title":"Postmeiotic sex chromatin in the male germline of mice","volume":"16","author":"Namekawa","year":"2006","journal-title":"Curr. Biol."},{"key":"2024061306360265700_DEV201501C26","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1101\/gad.1001502","article-title":"Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association","volume":"16","author":"Ng","year":"2002","journal-title":"Genes Dev."},{"key":"2024061306360265700_DEV201501C27","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cell.2005.02.020","article-title":"hDOT1L links histone methylation to leukemogenesis","volume":"121","author":"Okada","year":"2005","journal-title":"Cell"},{"key":"2024061306360265700_DEV201501C28","doi-asserted-by":"publisher","first-page":"8049","DOI":"10.1093\/nar\/10.24.8049","article-title":"Histone H4 hyperacetylation and rapid turnover of its acetyl groups in transcriptionally inactive rooster testis spermatids","volume":"10","author":"Oliva","year":"1982","journal-title":"Nucleic Acids Res."},{"key":"2024061306360265700_DEV201501C29","doi-asserted-by":"publisher","first-page":"6534","DOI":"10.1021\/bi3006972","article-title":"Multivalent recognition of histone tails by the PHD fingers of CHD5","volume":"51","author":"Oliver","year":"2012","journal-title":"Biochemistry"},{"key":"2024061306360265700_DEV201501C30","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s00412-013-0438-5","article-title":"Dynamics of DOT1L localization and H3K79 methylation during meiotic prophase I in mouse spermatocytes","volume":"123","author":"Ontoso","year":"2014","journal-title":"Chromosoma"},{"key":"2024061306360265700_DEV201501C31","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1023\/A:1018445520117","article-title":"A drying-down technique for the spreading of mammalian meiocytes from the male and female germline","volume":"5","author":"Peters","year":"1997","journal-title":"Chromosome Res."},{"key":"2024061306360265700_DEV201501C32","doi-asserted-by":"publisher","first-page":"5354","DOI":"10.1128\/MCB.23.15.5354-5365.2003","article-title":"Acetylation-dependent chromatin reorganization by BRDT, a testis-specific bromodomain-containing protein","volume":"23","author":"Pivot-Pajot","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2024061306360265700_DEV201501C33","doi-asserted-by":"publisher","first-page":"35659","DOI":"10.1074\/jbc.M109.038448","article-title":"AF17 competes with AF9 for binding to Dot1a to up-regulate transcription of epithelial Na+ channel alpha","volume":"284","author":"Reisenauer","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2024061306360265700_DEV201501C34","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/S1472-6483(10)60456-7","article-title":"Epigenetic reprogramming of the male genome during gametogenesis and in the zygote","volume":"16","author":"Rousseaux","year":"2008","journal-title":"Reprod. Biomed. Online"},{"key":"2024061306360265700_DEV201501C35","doi-asserted-by":"publisher","first-page":"3601","DOI":"10.1091\/mbc.11.10.3601","article-title":"Role for the silencing protein Dot1 in meiotic checkpoint control","volume":"11","author":"San-Segundo","year":"2000","journal-title":"Mol. Biol. Cell"},{"key":"2024061306360265700_DEV201501C36","doi-asserted-by":"publisher","first-page":"3507","DOI":"10.1242\/dev.004481","article-title":"The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation","volume":"134","author":"Shang","year":"2007","journal-title":"Development"},{"key":"2024061306360265700_DEV201501C37","doi-asserted-by":"publisher","first-page":"e1007952","DOI":"10.1371\/journal.pgen.1007952","article-title":"Dual functions for the ssDNA-binding protein RPA in meiotic recombination","volume":"15","author":"Shi","year":"2019","journal-title":"PLoS Genet."},{"key":"2024061306360265700_DEV201501C38","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/S0092-8674(02)00759-6","article-title":"Dot1p modulates silencing in yeast by methylation of the nucleosome core","volume":"109","author":"Van Leeuwen","year":"2002","journal-title":"Cell"},{"key":"2024061306360265700_DEV201501C39","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1007\/s00412-015-0570-5","article-title":"The upstreams and downstreams of H3K79 methylation by DOT1L","volume":"125","author":"Vlaming","year":"2016","journal-title":"Chromosoma"},{"key":"2024061306360265700_DEV201501C40","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1083\/jcb.200603063","article-title":"Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis","volume":"173","author":"Yang","year":"2006","journal-title":"J. Cell Biol."},{"key":"2024061306360265700_DEV201501C41","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1038\/nprot.2014.134","article-title":"Generating genetically modified mice using CRISPR\/Cas-mediated genome engineering","volume":"9","author":"Yang","year":"2014","journal-title":"Nat. Protoc."},{"key":"2024061306360265700_DEV201501C42","doi-asserted-by":"publisher","first-page":"e1002516","DOI":"10.1371\/journal.pgen.1002516","article-title":"MNS1 is essential for spermiogenesis and motile ciliary functions in mice","volume":"8","author":"Zhou","year":"2012","journal-title":"PLoS Genet."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.201501\/2793522\/dev201501.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.201501\/3487212\/dev201501.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.201501\/3487212\/dev201501.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T06:36:27Z","timestamp":1718260587000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/150\/9\/dev201501\/309501\/The-DOT1L-MLLT10-complex-regulates-male-fertility"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,1]]},"references-count":42,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2023,5,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.201501","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,1]]},"article-number":"dev201501"}}