title: Trim33 Binds and Silences a Class of Young Endogenous Retroviruses in the Mouse Testis; a Novel Component of the Arms Race between Retrotransposons and the Host Genome.
abstract: Transposable elements (TEs) have been active in the mammalian genome for millions of years and the silencing of these elements in the germline is important for the survival of the host. Mice carrying reporter transgenes can be used to model transcriptional silencing. A mutagenesis screen for modifiers of epigenetic gene silencing produced a line with a mutation in Trim33; the mutants displayed increased expression of the reporter transgene. ChIP-seq of Trim33 in testis revealed 9,109 peaks, mostly at promoters. This is the first report of ChIP-seq for Trim33 in any tissue. Comparison with ENCODE datasets showed that regions of high read density for Trim33 had high read density for histone marks associated with transcriptional activity and mapping to TE consensus sequences revealed Trim33 enrichment at RLTR10B, the LTR of one of the youngest retrotransposons in the mouse genome, MMERVK10C. We identified consensus sequences from the 266 regions at which Trim33 ChIP-seq peaks overlapped RLTR10B elements and found a match to the A-Myb DNA-binding site. We found that TRIM33 has E3 ubiquitin ligase activity for A-MYB and regulates its abundance. RNA-seq revealed that mice haploinsufficient for Trim33 had altered expression of a small group of genes in the testis and the gene with the most significant increase was found to be transcribed from an upstream RLTR10B. These studies provide the first evidence that A-Myb has a role in the actions of Trim33 and suggest a role for both A-Myb and Trim33 in the arms race between the transposon and the host. This the first report of any factor specifically regulating RLTR10B and adds to the current literature on the silencing of MMERVK10C retrotransposons. This is also the first report that A-Myb has a role in the transcription of any retrotransposon.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Isbel
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Rahul
authors.initials: R
authors.lastname: Srivastava
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Harald
authors.initials: H
authors.lastname: Oey
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Spurling
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Daxinger
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Hamsa
authors.initials: H
authors.lastname: Puthalakath
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
mesh_terms: D000818:Animals; D020868:Gene Silencing; D016678:Genome; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011485:Protein Binding; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D020079:Terminal Repeat Sequences; D013737:Testis / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D006657:Histones; C490283:Mybl1 protein, mouse; D020598:Proto-Oncogene Proteins c-myb; D018626:Retroelements; D015534:Trans-Activators; D014157:Transcription Factors; C491420:Trim33 protein, mouse; D044767:Ubiquitin-Protein Ligases