The distribution of a germline methylation marker suggests a regional mechanism of LINE-1 silencing by the piRNA-PIWI system

BMC Genetics

Jon J Jonsson²  Hans T Bjornsson³  Albert V Smith¹  Martin I Sigurdsson² 

[1] Icelandic Heart Association, Kopavogur IS-201, Iceland;Department of Genetics and Molecular Medicine, Landspitali-University Hospital, Reykjavik IS-101, Iceland;Harriet Lane Pediatric Residency Program, Baltimore, MD, USA

关键词: Epigenetics;    Methylation;    Germline;    Transposable element;    LINE-1;    PIWI;    piRNA;   

Others  :  1122470
DOI  :  10.1186/1471-2156-13-31

 received in 2011-11-28, accepted in 2012-04-24,  发布年份 2012

【 摘 要 】

Background

A defense system against transposon activity in the human germline based on PIWI proteins and piRNA has recently been discovered. It represses the activity of LINE-1 elements via DNA methylation by a largely unknown mechanism. Based on the dispersed distribution of clusters of piRNA genes in a strand-specific manner on all human chromosomes, we hypothesized that this system might work preferentially on local and proximal sequences. We tested this hypothesis with a methylation-associated SNP (mSNP) marker which is based on the density of C-T transitions in CpG dinucleotides as a surrogate marker for germline methylation.

Results

We found significantly higher density of mSNPs flanking piRNA clusters in the human genome for flank sizes of 1-16 Mb. A dose-response relationship between number of piRNA genes and mSNP density was found for up to 16 Mb of flanking sequences. The chromosomal density of hypermethylated LINE-1 elements had a significant positive correlation with the chromosomal density of piRNA genes (r = 0.41, P = 0.05). Genome windows of 1-16 Mb containing piRNA clusters had significantly more hypermethylated LINE-1 elements than windows not containing piRNA clusters. Finally, the minimum distance to the next piRNA cluster was significantly shorter for hypermethylated LINE-1 compared to normally methylated elements (14.4 Mb vs 16.1 Mb).

Conclusions

Our observations support our hypothesis that the piRNA-PIWI system preferentially methylates sequences in close proximity to the piRNA clusters and perhaps physically adjacent sequences on other chromosomes. Furthermore they suggest that this proximity effect extends up to 16 Mb. This could be due to an unknown localization signal, transcription of piRNA genes near the nuclear membrane or the presence of an unknown RNA molecule that spreads across the chromosome and targets the methylation directed by the piRNA-PIWI complex. Our data suggest a region specific molecular mechanism which can be sought experimentally.

【 授权许可】

   
2012 Sigurdsson et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Ehrlich M, Gama-Sosa MA, Huang LH, Midgett RM, Kuo KC, McCune RA, Gehrke C: Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res 1982, 10:2709-2721.
• [2]Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo Q, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR: Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 2009, 462:315-322.
• [3]Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H: Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 2004, 429:900-903.
• [4]Okano M, Xie S, Li E: Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 1998, 19:219-220.
• [5]Song F, Smith JF, Kimura MT, Morrow AD, Matsuyama T, Nagase H, Held WA: Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. Proc Natl Acad Sci USA 2005, 102:3336-3341.
• [6]Weber M, Hellmann I, Stadler MB, Ramos L, Pääbo S, Rebhan M, Schübeler D: Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 2007, 39:457-466.
• [7]Reik W, Walter J: Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001, 2:21-32.
• [8]Hellman A, Chess A: Gene body-specific methylation on the active X chromosome. Science (80-) 2007, 315:1141-1143.
• [9]Venolia L, Gartler SM, Wassman ER, Yen P, Mohandas T, Shapiro LJ: Transformation with DNA from 5-azacytidine-reactivated X chromosomes. Proc Natl Acad Sci USA 1982, 79:2352-2354.
• [10]Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, et al.: Initial sequencing and analysis of the human genome. Nature 2001, 409:860-921.
• [11]Hedges DJ, Deininger PL: Inviting instability: transposable elements, double-strand breaks, and the maintenance of genome integrity. Mutat Res 2007, 616:46-59.
• [12]Zamudio N, Bourc'his D: Transposable elements in the mammalian germline: a comfortable niche or a deadly trap? Heredity 2010, 105:92-104.
• [13]Yoder JA, Walsh CP, Bestor TH: Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 1997, 13:335-340.
• [14]Bird A: Does DNA methylation control transposition of selfish elements in the germline? Trends Genet 1997, 13:469-472.
• [15]Bogerd HP, Wiegand HL, Doehle BP, Lueders KK, Cullen BR: APOBEC3A and APOBEC3B are potent inhibitors of LTR-retrotransposon function in human cells. Nucleic Acids Res 2006, 34:89-95.
• [16]Hulme AE, Bogerd HP, Cullen BR, Moran JV: Selective inhibition of Alu retrotransposition by APOBEC3G. Gene 2007, 390:199-205.
• [17]Hata K, Sakaki Y: Identification of critical CpG sites for repression of L1 transcription by DNA methylation. Gene 1997, 189:227-234.
• [18]Bourc'his D, Bestor TH: Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 2004, 431:96-99.
• [19]Aravin AA, Naumova NM, Tulin AV, Vagin VV, Rozovsky YM, Gvozdev VA: Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr Biol 2001, 11:1017-1027.
• [20]Girard A, Sachidanandam R, Hannon GJ, Carmell MA: A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 2006, 442:199-202.
• [21]Carmell MA, Girard A, van de Kant HJG, Bourc'his D, Bestor TH, de Rooij DG, Hannon GJ: MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline. Dev Cell 2007, 12:503-514.
• [22]Kuramochi-Miyagawa S, Watanabe T, Gotoh K, Totoki Y, Toyoda A, Ikawa M, Asada N, Kojima K, Yamaguchi Y, Ijiri TW, Hata K, Li E, Matsuda Y, Kimura T, Okabe M, Sakaki Y, Sasaki H, Nakano T: DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in murine fetal testes. Genes Dev 2008, 22:908-917.
• [23]Shoji M, Tanaka T, Hosokawa M, Reuter M, Stark A, Kato Y, Kondoh G, Okawa K, Chujo T, Suzuki T, Hata K, Martin SL, Noce T, Kuramochi-Miyagawa S, Nakano T, Sasaki H, Pillai RS, Nakatsuji N, Chuma S: The TDRD9-MIWI2 complex is essential for piRNA-mediated retrotransposon silencing in the mouse male germline. Dev Cell 2009, 17:775-787.
• [24]Siddiqi S, Matushansky I: Piwis and piwi-interacting RNAs in the epigenetics of cancer. J Cell Biochem 2012, 113:373-380.
• [25]Qiao D, Zeeman A, Deng W, Looijenga LHJ, Lin H: Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas. Oncogene 2002, 21:3988-3999.
• [26]Taubert H, Greither T, Kaushal D, Würl P, Bache M, Bartel F, Kehlen A, Lautenschläger C, Harris L, Kraemer K, Meye A, Kappler M, Schmidt H, Holzhausen H, Hauptmann S: Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma. Oncogene 2007, 26:1098-1100.
• [27]Sigurdsson MI, Smith AV, Bjornsson HT, Jonsson JJ: HapMap methylation-associated SNPs, markers of germline DNA methylation, positively correlate with regional levels of human meiotic recombination. Genome Res 2009, 19:581-589.
• [28]Jähner D, Jaenisch R: Retrovirus-induced de novo methylation of flanking host sequences correlates with gene inactivity. Nature 1985, 315:594-597.
• [29]Lee JT: The X as model for RNA's niche in epigenomic regulation. Cold Spring Harb Perspect Biol 2010, 2:a003749.
• [30]International HapMap Consortium: A second generation human haplotype map of over 3.1 million SNPs. Nature 2007, 449:851-861.
• [31]Thomas DJ, Trumbower H, Kern AD, Rhead BL, Kuhn RM, Haussler D, Kent WJ: Variation resources at UC Santa Cruz. Nucleic Acids Res 2007, 35:D716-D720.
• [32]Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D: The human genome browser at UCSC. Genome Res 2002, 12:996-1006.
• [33]Jurka J, Kapitonov VV, Pavlicek A, Klonowski P, Kohany O, Walichiewicz J: Repbase Update, a database of eukaryotic repetitive elements. Cytogenet Genome Res 2005, 110:462-467.
• [34]Karolchik D, Hinrichs AS, Furey TS, Roskin KM, Sugnet CW, Haussler D, Kent WJ: The UCSC Table Browser data retrieval tool. Nucleic Acids Res 2004, 32:D493-D496.