title: DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs.
abstract: DNA methylation and histone H3 lysine 9 trimethylation (H3K9me3) play important roles in silencing of genes and retroelements. However, a comprehensive comparison of genes and repetitive elements repressed by these pathways has not been reported. Here we show that in mouse embryonic stem cells (mESCs), the genes upregulated after deletion of the H3K9 methyltransferase Setdb1 are distinct from those derepressed in mESC deficient in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b, with the exception of a small number of primarily germline-specific genes. Numerous endogenous retroviruses (ERVs) lose H3K9me3 and are concomitantly derepressed exclusively in SETDB1 knockout mESCs. Strikingly, ~15% of upregulated genes are induced in association with derepression of promoter-proximal ERVs, half in the context of "chimeric" transcripts that initiate within these retroelements and splice to genic exons. Thus, SETDB1 plays a previously unappreciated yet critical role in inhibiting aberrant gene transcription by suppressing the expression of proximal ERVs.
authors.affiliation: Department of Medical Genetics, Life Sciences Institute, The University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Karimi
authors.forename: Preeti
authors.initials: P
authors.lastname: Goyal
authors.forename: Irina A
authors.initials: IA
authors.lastname: Maksakova
authors.forename: Misha
authors.initials: M
authors.lastname: Bilenky
authors.forename: Danny
authors.initials: D
authors.lastname: Leung
authors.forename: Jie Xin
authors.initials: JX
authors.lastname: Tang
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shinkai
authors.forename: Dixie L
authors.initials: DL
authors.lastname: Mager
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Lorincz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D053595:Embryonic Stem Cells / Q000201:enzymology / Q000378:metabolism* / Q000821:virology; D020077:Endogenous Retroviruses / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011496:Protein Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018626:Retroelements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones; D008239:Lysine; D011496:Protein Methyltransferases; D018626:Retroelements; D000097584:DNA Methyltransferase 3B; C000715535:Dnmt3a protein, mouse; C000619381:Dnmt1 protein, mouse; C516239:SETDB1 protein, mouse