Distinct roles of DNMT1-dependent and DNMT1-independent methylation patterns in the genome of mouse embryonic stem cells
Tóm tắt
DNA methylation patterns are initiated by de novo DNA methyltransferases DNMT3a/3b adding methyl groups to CG dinucleotides in the hypomethylated genome of early embryos. These patterns are faithfully maintained by DNMT1 during DNA replication to ensure epigenetic inheritance across generations. However, this two-step model is based on limited data. We generated base-resolution DNA methylomes for a series of DNMT knockout embryonic stem cells, with deep coverage at highly repetitive elements. We show that DNMT1 and DNMT3a/3b activities work complementarily and simultaneously to establish symmetric CG methylation and CHH (H = A, T or C) methylation. DNMT3a/3b can add methyl groups to daughter strands after each cycle of DNA replication. We also observe an unexpected division of labor between DNMT1 and DNMT3a/3b in suppressing retrotransposon long terminal repeats and long interspersed elements, respectively. Our data suggest that mammalian cells use a specific CG density threshold to predetermine methylation levels in wild-type cells and the magnitude of methylation reduction in DNMT knockout cells. Only genes with low CG density can be induced or, surprisingly, suppressed in the hypomethylated genome. Lastly, we do not find any association between gene body methylation and transcriptional activity. We show the concerted actions of DNMT enzymes in the establishment and maintenance of methylation patterns. The finding of distinct roles of DNMT1-dependent and -independent methylation patterns in genome stability and regulation of transcription provides new insights for understanding germ cell development, neuronal diversity, and transgenerational epigenetic inheritance and will help to develop next-generation DNMT inhibitors.
Tài liệu tham khảo
Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304.
Probst AV, Dunleavy E, Almouzni G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol. 2009;10:192–206.
Ferguson-Smith AC. Genomic imprinting: the emergence of an epigenetic paradigm. Nat Rev Genet. 2011;12:565–75.
Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science. 2010;330:622–7.
Cedar H, Bergman Y. Programming of DNA methylation patterns. Annu Rev Biochem. 2012;81:97–117.
Chang G, Gao S, Hou X, Xu Z, Liu Y, Kang L, et al. High-throughput sequencing reveals the disruption of methylation of imprinted gene in induced pluripotent stem cells. Cell Res. 2014;24:293–306.
Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11:726–34.
Varley KE, Gertz J, Bowling KM, Parker SL, Reddy TE, Pauli-Behn F, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 2013;23:555–67.
Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–22.
Liang G, Chan MF, Tomigahara Y, Tsai YC, Gonzales FA, Li E, et al. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol Cell Biol. 2002;22:480–91.
Arand J, Spieler D, Karius T, Branco MR, Meilinger D, Meissner A, et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 2012;8, e1002750.
Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM. DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011;108:3630–5.
Jones PA, Liang G. Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009;10:805–11.
Seisenberger S, Popp C, Reik W. Retrotransposons and germ cells: reproduction, death, and diversity. F1000 Biol Rep. 2010;2:44.
Goodier JL, Kazazian Jr HH. Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell. 2008;135:23–35.
Chen JM, Chuzhanova N, Stenson PD, Ferec C, Cooper DN. Meta-analysis of gross insertions causing human genetic disease: novel mutational mechanisms and the role of replication slippage. Hum Mutat. 2005;25:207–21.
Kazazian Jr HH, Moran JV. The impact of L1 retrotransposons on the human genome. Nat Genet. 1998;19:19–24.
Maksakova IA, Romanish MT, Gagnier L, Dunn CA, van de Lagemaat LN, Mager DL. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2006;2, e2.
Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, et al. L1 retrotransposition in human neural progenitor cells. Nature. 2009;460:1127–31.
Walsh CP, Chaillet JR, Bestor TH. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet. 1998;20:116–7.
Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J, et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis. 2003;35:88–93.
Barker DJ. The developmental origins of adult disease. Eur J Epidemiol. 2003;18:733–6.
Martos SN, Tang WY, Wang Z. Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease. Prog Biophys Mol Biol. 2015;10.1016/j.pbiomolbio. 2015.02.011.
Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114:567–72.
Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A. 2007;104:13056–61.
Stein R, Razin A, Cedar H. In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc Natl Acad Sci U S A. 1982;79:3418–22.
Siegfried Z, Eden S, Mendelsohn M, Feng X, Tsuberi BZ, Cedar H. DNA methylation represses transcription in vivo. Nat Genet. 1999;22:203–6.
Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat Biotechnol. 2010;28:1069–78.
Chik F, Szyf M. Effects of specific DNMT gene depletion on cancer cell transformation and breast cancer cell invasion; toward selective DNMT inhibitors. Carcinogenesis. 2011;32:224–32.
Wu H, Coskun V, Tao J, Xie W, Ge W, Yoshikawa K, et al. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes. Science. 2010;329:444–8.
Karimi MM, Goyal P, Maksakova IA, Bilenky M, Leung D, Tang JX, et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell. 2011;8:676–87.
Li E, Beard C, Jaenisch R. Role for DNA methylation in genomic imprinting. Nature. 1993;366:362–5.
Tsumura A, Hayakawa T, Kumaki Y, Takebayashi S, Sakaue M, Matsuoka C, et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells. 2006;11:805–14.
Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–57.
Spada F, Haemmer A, Kuch D, Rothbauer U, Schermelleh L, Kremmer E, et al. DNMT1 but not its interaction with the replication machinery is required for maintenance of DNA methylation in human cells. J Cell Biol. 2007;176:565–71.
Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Scholer A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–5.
Meilinger D, Fellinger K, Bultmann S, Rothbauer U, Bonapace IM, Klinkert WE, et al. Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO Rep. 2009;10:1259–64.
Huff JT, Zilberman D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell. 2014;156:1286–97.
Mandal PK, Kazazian Jr HH. SnapShot: Vertebrate transposons. Cell. 2008;135:192–2. e191.
Jeong S, Liang G, Sharma S, Lin JC, Choi SH, Han H, et al. Selective anchoring of DNA methyltransferases 3A and 3B to nucleosomes containing methylated DNA. Mol Cell Biol. 2009;29:5366–76.
Jeong M, Sun D, Luo M, Huang Y, Challen GA, Rodriguez B, et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat Genet. 2014;46:17–23.
Smith ZD, Chan MM, Mikkelsen TS, Gu H, Gnirke A, Regev A, et al. A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012;484:339–44.
Molaro A, Hodges E, Fang F, Song Q, McCombie WR, Hannon GJ, et al. Sperm methylation profiles reveal features of epigenetic inheritance and evolution in primates. Cell. 2011;146:1029–41.
La Salle S, Mertineit C, Taketo T, Moens PB, Bestor TH, Trasler JM. Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev Biol. 2004;268:403–15.
Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nat Genet. 1999;23:314–8.
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–6.
McGarvey KM, Fahrner JA, Greene E, Martens J, Jenuwein T, Baylin SB. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res. 2006;66:3541–9.
Ohm JE, Baylin SB. Stem cell chromatin patterns: an instructive mechanism for DNA hypermethylation? Cell Cycle. 2007;6:1040–3.
Lorincz MC, Dickerson DR, Schmitt M, Groudine M. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol. 2004;11:1068–75.
Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell. 2014;26:577–90.
Wagner JR, Busche S, Ge B, Kwan T, Pastinen T, Blanchette M. The relationship between DNA methylation, genetic and expression inter-individual variation in untransformed human fibroblasts. Genome Biol. 2014;15:R37.
Linhart HG, Lin H, Yamada Y, Moran E, Steine EJ, Gokhale S, et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 2007;21:3110–22.
Roll JD, Rivenbark AG, Jones WD, Coleman WB. DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer. 2008;7:15.
Lei H, Oh SP, Okano M, Juttermann R, Goss KA, Jaenisch R, et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development. 1996;122:3195–205.
Warnecke PM, Stirzaker C, Melki JR, Millar DS, Paul CL, Clark SJ. Detection and measurement of PCR bias in quantitative methylation analysis of bisulphite-treated DNA. Nucleic Acids Res. 1997;25:4422–6.
Lee WP, Stromberg MP, Ward A, Stewart C, Garrison EP, Marth GT. MOSAIK: a hash-based algorithm for accurate next-generation sequencing short-read mapping. PLoS One. 2014;9, e90581.
Otto C, Stadler PF, Hoffmann S. Fast and sensitive mapping of bisulfite-treated sequencing data. Bioinformatics. 2012;28:1698–704.
Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10:R25.
Smit AFA, Hubley R, Green P. RepeatMasker Open-4.0. 2013–2015. http://www.repeatmasker.org.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.
Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL, Pachter L. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2013;31:46–53.