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Không có bằng chứng về tác động tích lũy trong một dạng đột biến Dnmt3b qua nhiều thế hệ
Tóm tắt
Các quan sát về các kiểu hình thừa kế không thể được giải thích chỉ bằng di truyền học đang gia tăng. Bằng chứng chỉ ra rằng sự truyền tải các phân tử không phải DNA trong giao tử là trung gian của các kiểu hình. Tuy nhiên, trong hầu hết các trường hợp, không rõ các phân tử đó là gì, với metyl hóa DNA, protein nhiễm sắc thể và RNA nhỏ là những ứng viên nổi bật nhất. Từ một phương pháp sàng lọc để tạo ra các đột biến chuột mới của các gen liên quan đến tái lập trình di truyền biểu sinh, chúng tôi đã tạo ra một allele DNA metyltransferase 3b bị thiếu exon 13. Những con chuột homozygous mang allele đột biến có kích thước nhỏ hơn và độ sống sót giảm, với tỷ lệ tử vong hậu sinh nữ rất cao. Giảm metyl hóa DNA cũng được phát hiện ở các đoạn lặp telocentric và gen Hprt liên kết với X. Tuy nhiên, không có bất kỳ kiểu hình bất thường hay thay đổi metyl hóa DNA nào trở nên nghiêm trọng hơn với việc giao phối cận huyết nhiều thế hệ của các đột biến homozygous. Điều này cho thấy trong mô hình của chúng tôi, các bất thường được thiết lập lại ở mỗi thế hệ và các quá trình tái lập trình di truyền biểu sinh xuyên thế hệ có hiệu quả trong việc ngăn chặn sự thừa kế của chúng.
Từ khóa
#di truyền biểu sinh #đột biến Dnmt3b #metyl hóa DNA #kiểu hình thừa kế #tái lập trình di truyềnTài liệu tham khảo
Argentaro A, Yang JC, Chapman L, Kowalczyk MS, Gibbons RJ, Higgs DR, Neuhaus D, Rhodes D (2007) Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX. Proc Natl Acad Sci USA 104:11939–11944
Ashe A, Morgan DK, Whitelaw NC, Bruxner TJ, Vickaryous NK, Cox LL, Butterfield NC, Wicking C, Blewitt ME, Wilkins SJ, Anderson GJ, Cox TC, Whitelaw E (2008) A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biol 9:R182
Biniszkiewicz D, Gribnau J, Ramsahoye B, Gaudet F, Eggan K, Humpherys D, Mastrangelo MA, Jun Z, Walter J, Jaenisch R (2002) Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol 22:2124–2135
Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ, Preis JI, Arkell R, Whitelaw E (2005) An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc Natl Acad Sci USA 102:7629–7634
Bock C, Reither S, Mikeska T, Paulsen M, Walter J, Lengauer T (2005) BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. Bioinformatics 21:4067–4068
Bohacek J, Gapp K, Saab BJ, Mansuy IM (2013) Transgenerational epigenetic effects on brain functions. Biol Psychiatry 73(4):313–320
Bourc’his D, Miniou P, Jeanpierre M, Molina Gomes D, Dupont J, De Saint-Basile G, Maraschio P, Tiepolo L, Viegas-Pequignot E (1999) Abnormal methylation does not prevent X inactivation in ICF patients. Cytogenet Cell Genet 84:245–252
Brykczynska U, Hisano M, Erkek S, Ramos L, Oakeley EJ, Roloff TC, Beisel C, Schubeler D, Stadler MB, Peters AH (2010) Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat Struct Mol Biol 17:679–687
Chong S, Vickaryous N, Ashe A, Zamudio N, Youngson N, Hemley S, Stopka T, Skoultchi A, Matthews J, Scott HS, de Kretser D, O’Bryan M, Blewitt M, Whitelaw E (2007) Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet 39:614–622
Danchin E, Charmantier A, Champagne FA, Mesoudi A, Pujol B, Blanchet S (2011) Beyond DNA: integrating inclusive inheritance into an extended theory of evolution. Nat Rev Genet 12:475–486
Daxinger L, Whitelaw E (2012) Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet 13:153–162
Daxinger L, Oey H, Apedaile A, Sutton J, Ashe A, Whitelaw E (2012) A forward genetic screen identifies eukaryotic translation initiation factor 3, subunit H (eIF3h), as an enhancer of variegation in the mouse. G3 (Bethesda) 2:1393–1396
Dhayalan A, Tamas R, Bock I, Tattermusch A, Dimitrova E, Kudithipudi S, Ragozin S, Jeltsch A (2011) The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9. Hum Mol Genet 20:2195–2203
Gartler SM, Varadarajan KR, Luo P, Canfield TK, Traynor J, Francke U, Hansen RS (2004) Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins. BMC Biol 2:21
Gendrel AV, Apedaile A, Coker H, Termanis A, Zvetkova I, Godwin J, Tang YA, Huntley D, Montana G, Taylor S, Giannoulatou E, Heard E, Stancheva I, Brockdorff N (2012) Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev Cell 23:265–279
Grandjean V, Gounon P, Wagner N, Martin L, Wagner KD, Bernex F, Cuzin F, Rassoulzadegan M (2009) The miR-124-Sox9 paramutation: RNA-mediated epigenetic control of embryonic and adult growth. Development 136:3647–3655
Guenatri M, Bailly D, Maison C, Almouzni G (2004) Mouse centric and pericentric satellite repeats form distinct functional heterochromatin. J Cell Biol 166:493–505
Guerrero-Bosagna C, Skinner MK (2012) Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Mol Cell Endocrinol 354:3–8
Guerrero-Bosagna C, Settles M, Lucker B, Skinner MK (2010) Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One 5(9):e13100. doi:10.1371/journal.pone.0013100
Guibert S, Forne T, Weber M (2012) Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res 22:633–641
Hadchouel M, Farza H, Simon D, Tiollais P, Pourcel C (1987) Maternal inhibition of hepatitis B surface antigen gene expression in transgenic mice correlates with de novo methylation. Nature 329:454–456
Hagleitner MM, Lankester A, Maraschio P, Hulten M, Fryns JP, Schuetz C, Gimelli G, Davies EG, Gennery A, Belohradsky BH, de Groot R, Gerritsen EJ, Mattina T, Howard PJ, Fasth A, Reisli I, Furthner D, Slatter MA, Cant AJ, Cazzola G, van Dijken PJ, van Deuren M, de Greef JC, van der Maarel SM, Weemaes CM (2008) Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 45:93–99
Hammoud SS, Nix DA, Zhang H, Purwar J, Carrell DT, Cairns BR (2009) Distinctive chromatin in human sperm packages genes for embryo development. Nature 460:473–478
Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM (1999) The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci USA 96:14412–14417
Heyn H, Vidal E, Sayols S, Sanchez-Mut JV, Moran S, Medina I, Sandoval J, Simo-Riudalbas L, Szczesna K, Huertas D, Gatto S, Matarazzo MR, Dopazo J, Esteller M (2012) Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient. Epigenetics 7:542–550
Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD (2008) DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 17:690–709
Juriloff DM, Harris MJ (2012) Hypothesis: the female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating X chromosome on the molecular mechanisms of neural fold elevation. Birth Defects Res A Clin Mol Teratol 94:849–855
Kalitsis P, Griffiths B, Choo KH (2006) Mouse telocentric sequences reveal a high rate of homogenization and possible role in Robertsonian translocation. Proc Natl Acad Sci USA 103:8786–8791
Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H (2004) Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903
Li E, Bestor TH, Jaenisch R (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926
Li JY, Lees-Murdock DJ, Xu GL, Walsh CP (2004) Timing of establishment of paternal methylation imprints in the mouse. Genomics 84:952–960
Liu WM, Pang RT, Chiu PC, Wong BP, Lao K, Lee KF, Yeung WS (2012) Sperm-borne microRNA-34c is required for the first cleavage division in mouse. Proc Natl Acad Sci USA 109:490–494
Morgan HD, Sutherland HG, Martin DI, Whitelaw E (1999) Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23:314–318
Nelson VR, Nadeau JH (2010) Transgenerational genetic effects. Epigenomics 2:797–806
Neuhaus IM, Beier DR (1998) Efficient localization of mutations by interval haplotype analysis. Mamm Genome 9(2):150–154
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257
Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448:714–717
Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M, Shirakawa M (2009) Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep 10:1235–1241
Preis JI, Downes M, Oates NA, Rasko JE, Whitelaw E (2003) Sensitive flow cytometric analysis reveals a novel type of parent-of-origin effect in the mouse genome. Curr Biol 13:955–959
Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, Cuzin F (2006) RNA-mediated non-Mendelian inheritance of an epigenetic change in the mouse. Nature 441:469–474
Sutherland HG, Kearns M, Morgan HD, Headley AP, Morris C, Martin DI, Whitelaw E (2000) Reactivation of heritably silenced gene expression in mice. Mamm Genome 11:347–355
Tada M, Tada T, Lefebvre L, Barton SC, Surani MA (1997) Embryonic germ cells induce epigenetic reprogramming of somatic nucleus in hybrid cells. EMBO J 16:6510–6520
Takada S, Paulsen M, Tevendale M, Tsai CE, Kelsey G, Cattanach BM, Ferguson-Smith AC (2002) Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum Mol Genet 11:77–86
Ueda Y, Okano M, Williams C, Chen T, Georgopoulos K, Li E (2006) Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome. Development 133:1183–1192
Velasco G, Hubé F, Rollin J, Neuillet D, Philippe C, Bouzinba-Segard H, Galvani A, Viegas-Péquignot E, Francastel C (2010) Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues. Proc Natl Acad Sci USA 107(20):9281–9286
Watanabe T, Tomizawa S, Mitsuya K, Totoki Y, Yamamoto Y, Kuramochi-Miyagawa S, Iida N, Hoki Y, Murphy PJ, Toyoda A, Gotoh K, Hiura H, Arima T, Fujiyama A, Sado T, Shibata T, Nakano T, Lin H, Ichiyanagi K, Soloway PD, Sasaki H (2011) Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus. Science 332:848–852
Whitelaw NC, Chong S, Morgan DK, Nestor C, Bruxner TJ, Ashe A, Lambley E, Meehan R, Whitelaw E (2010) Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise. Genome Biol 11:R111
Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Péquignot E (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402(6758):187–191
Youngson N (2012) Challenges and future prospects for non-genetic inheritance. Nongenet Inherit 1:1–8
Youngson NA, Whitelaw E (2008) Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 9:233–257
Youngson NA, Vickaryous N, van der Horst A, Epp T, Harten S, Fleming JS, Khanna KK, de Kretser DM, Whitelaw E (2011) A missense mutation in the transcription factor Foxo3a causes teratomas and oocyte abnormalities in mice. Mamm Genome 22:235–248
Zhang Y, Jurkowska R, Soeroes S, Rajavelu A, Dhayalan A, Bock I, Rathert P, Brandt O, Reinhardt R, Fischle W, Jeltsch A (2010) Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail. Nucleic Acids Res 38:4246–4253