Epigenetic inheritance is unfaithful at intermediately methylated CpG sites.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 09 2023
02 09 2023
Historique:
received:
14
03
2023
accepted:
12
08
2023
medline:
4
9
2023
pubmed:
3
9
2023
entrez:
2
9
2023
Statut:
epublish
Résumé
DNA methylation at the CpG dinucleotide is considered a stable epigenetic mark due to its presumed long-term inheritance through clonal expansion. Here, we perform high-throughput bisulfite sequencing on clonally derived somatic cell lines to quantitatively measure methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity, and is not coordinately maintained between neighbouring sites. We determine that the probabilistic changes that occur at intermediately methylated sites are likely due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the current epigenetic inheritance model and has direct implications for both the functional relevance and general interpretability of DNA methylation as a stable epigenetic mark.
Identifiants
pubmed: 37660134
doi: 10.1038/s41467-023-40845-2
pii: 10.1038/s41467-023-40845-2
pmc: PMC10475082
doi:
Substances chimiques
Nucleotides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5336Subventions
Organisme : Wellcome Trust
ID : 210757/Z/18/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R009791/1
Pays : United Kingdom
Informations de copyright
© 2023. Springer Nature Limited.
Références
Robertson, K. D. DNA methylation and human disease. Nat. Rev. Genet. 6, 597–610 (2005).
pubmed: 16136652
Smith, Z. D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).
pubmed: 23400093
Holliday, R. DNA methylation and epigenetic inheritance. Philos. Trans. R. Soc. Lond. B Biol. Sci. 326, 329–338 (1990).
pubmed: 1968668
Bestor, T. H. & Tycko, B. Creation of genomic methylation patterns. Nat. Genet. 12, 363–367 (1996).
pubmed: 8630488
Probst, A. V., Dunleavy, E. & Almouzni, G. Epigenetic inheritance during the cell cycle. Nat. Rev. Mol. Cell Biol. 10, 192–206 (2009).
pubmed: 19234478
Kim, M. & Costello, J. DNA methylation: an epigenetic mark of cellular memory. Exp. Mol. Med. 49, e322 (2017).
pubmed: 28450738
pmcid: 6130213
Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, https://doi.org/10.1126/science.aaj2239 (2017).
Pfeifer, G. P., Steigerwald, S. D., Hansen, R. S., Gartler, S. M. & Riggs, A. D. Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. Proc. Natl Acad. Sci. USA 87, 8252–8256 (1990).
pubmed: 2236038
pmcid: 54933
Turker, M. S., Swisshelm, K., Smith, A. C. & Martin, G. M. A partial methylation profile for a CpG site is stably maintained in mammalian tissues and cultured cell lines. J. Biol. Chem. 264, 11632–11636 (1989).
pubmed: 2545677
Arand, J. et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 8, e1002750 (2012).
pubmed: 22761581
pmcid: 3386304
Zhao, L. et al. The dynamics of DNA methylation fidelity during mouse embryonic stem cell self-renewal and differentiation. Genome Res. 24, 1296–1307 (2014).
pubmed: 24835587
pmcid: 4120083
Shipony, Z. et al. Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells. Nature 513, 115–119 (2014).
pubmed: 25043040
Waterland, R. A. & Jirtle, R. L. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol. Cell. Biol. 23, 5293–5300 (2003).
pubmed: 12861015
pmcid: 165709
Waterland, R. A. et al. Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 44, 401–406 (2006).
pubmed: 16868943
Bertozzi, T. M. & Ferguson-Smith, A. C. Metastable epialleles and their contribution to epigenetic inheritance in mammals. Semin. Cell Dev. Biol. 97, 93–105 (2020).
pubmed: 31551132
Jeltsch, A. & Jurkowska, R. Z. New concepts in DNA methylation. Trends Biochem. Sci. 39, 310–318 (2014).
pubmed: 24947342
Jones, P. A. & Liang, G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 10, 805–811 (2009).
pubmed: 19789556
pmcid: 2848124
Edwards, J. R. et al. Chromatin and sequence features that define the fine and gross structure of genomic methylation patterns. Genome Res. 20, 972–980 (2010).
pubmed: 20488932
pmcid: 2892098
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).
pubmed: 18600261
pmcid: 2896277
Eckhardt, F. et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat. Genet. 38, 1378–1385 (2006).
pubmed: 17072317
pmcid: 3082778
Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33(Suppl.), 245–254 (2003).
pubmed: 12610534
Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9, 465–476 (2008).
pubmed: 18463664
Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).
pubmed: 15952895
Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116–117 (1998).
pubmed: 9771701
Ferrigno, O. et al. Transposable B2 SINE elements can provide mobile RNA polymerase II promoters. Nat. Genet. 28, 77–81 (2001).
pubmed: 11326281
Jordan, I. K., Rogozin, I. B., Glazko, G. V. & Koonin, E. V. Origin of a substantial fraction of human regulatory sequences from transposable elements. Trends Genet. 19, 68–72 (2003).
pubmed: 12547512
Zhou, W., Liang, G., Molloy, P. L. & Jones, P. A. DNA methylation enables transposable element-driven genome expansion. Proc. Natl Acad. Sci. USA 117, 19359–19366 (2020).
pubmed: 32719115
pmcid: 7431005
Hansen, K. H. et al. A model for transmission of the H3K27me3 epigenetic mark. Nat. Cell Biol. 10, 1291–1300 (2008).
pubmed: 18931660
Hathaway, N. A. et al. Dynamics and memory of heterochromatin in living cells. Cell 149, 1447–1460 (2012).
pubmed: 22704655
pmcid: 3422694
Karmodiya, K., Krebs, A. R., Oulad-Abdelghani, M., Kimura, H. & Tora, L. H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells. BMC Genom. 13, 424 (2012).
Shen, Y. et al. A map of the cis-regulatory sequences in the mouse genome. Nature 488, 116–120 (2012).
pubmed: 22763441
pmcid: 4041622
Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40, 897–903 (2008).
pubmed: 18552846
pmcid: 2769248
Kolasinska-Zwierz, P. et al. Differential chromatin marking of introns and expressed exons by H3K36me3. Nat. Genet. 41, 376–381 (2009).
pubmed: 19182803
pmcid: 2648722
Dahlet, T. et al. Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity. Nat. Commun. 11, 3153 (2020).
pubmed: 32561758
pmcid: 7305168
Berdasco, M. & Esteller, M. Clinical epigenetics: seizing opportunities for translation. Nat. Rev. Genet. 20, 109–127 (2019).
pubmed: 30479381
Dominguez-Salas, P. et al. Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. Nat. Commun. 5, 3746 (2014).
pubmed: 24781383
Levine, M. E. et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany, NY) 10, 573–591 (2018).
pubmed: 29676998
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
pubmed: 29643443
Issa, J. P. Aging and epigenetic drift: a vicious cycle. J. Clin. Investig. 124, 24–29 (2014).
pubmed: 24382386
pmcid: 3871228
Charlton, J. et al. Global delay in nascent strand DNA methylation. Nat. Struct. Mol. Biol. 25, 327–332 (2018).
pubmed: 29531288
pmcid: 5889353
Ming, X. et al. Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration. Cell Res. 30, 980–996 (2020).
pubmed: 32581343
pmcid: 7785024
Stewart-Morgan, K. R. et al. Quantifying propagation of DNA methylation and hydroxymethylation with iDEMS. Nat. Cell Biol. 25, 183–193 (2023).
pubmed: 36635504
pmcid: 9859752
Haggerty, C. et al. Dnmt1 has de novo activity targeted to transposable elements. Nat. Struct. Mol. Biol. 28, 594–603 (2021).
pubmed: 34140676
pmcid: 8279952
Li, Y. et al. Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1. Nature 564, 136–140 (2018).
pubmed: 30487604
Wang, Q. et al. Imprecise DNMT1 activity coupled with neighbor-guided correction enables robust yet flexible epigenetic inheritance. Nat. Genet. 52, 828–839 (2020).
pubmed: 32690947
Yarychkivska, O., Shahabuddin, Z., Comfort, N., Boulard, M. & Bestor, T. H. BAH domains and a histone-like motif in DNA methyltransferase 1 (DNMT1) regulate de novo and maintenance methylation in vivo. J. Biol. Chem. 293, 19466–19475 (2018).
pubmed: 30341171
pmcid: 6302165
Dodge, J. E. et al. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J. Biol. Chem. 280, 17986–17991 (2005).
pubmed: 15757890
Qiu, L. Q., Lai, W. S., Stumpo, D. J. & Blackshear, P. J. Mouse embryonic fibroblast cell culture and stimulation. Bio Protoc. 6, https://doi.org/10.21769/BioProtoc.1859 (2016).
Todaro, G. J. & Green, H. Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J. Cell Biol. 17, 299–313 (1963).
pubmed: 13985244
pmcid: 2106200
Krueger, F. & Andrews, S. R. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27, 1571–1572 (2011).
pubmed: 21493656
pmcid: 3102221
Hansen, K. D., Langmead, B. & Irizarry, R. A. BSmooth: from whole genome bisulfite sequencing reads to differentially methylated regions. Genome Biol. 13, R83 (2012).
pubmed: 23034175
pmcid: 3491411
Sapozhnikov, D. M. & Szyf, M. Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9. Nat. Commun. 12, 5711 (2021).
pubmed: 34588447
pmcid: 8481236
Schafer, A. et al. Impaired DNA demethylation of C/EBP sites causes premature aging. Genes Dev. 32, 742–762 (2018).
pubmed: 29884649
pmcid: 6049513
Luo, Y. et al. New developments on the Encyclopedia of DNA Elements (ENCODE) data portal. Nucleic Acids Res. 48, D882–D889 (2020).
pubmed: 31713622
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A. & Kingsford, C. Salmon provides fast and bias-aware quantification of transcript expression. Nat. Methods 14, 417–419 (2017).
pubmed: 28263959
pmcid: 5600148
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049