Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).
Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes. Dev. 25, 1010–1022 (2011).
Smallwood, S. A. et al. Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat. Methods 11, 817–820 (2014).
Farlik, M. et al. Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics. Cell Rep. 10, 1386–1397 (2015).
Argelaguet, R. et al. Multi-omics profiling of mouse gastrulation at single-cell resolution. Nature 576, 487–491 (2019).
Ziller, M. J. et al. Charting a dynamic DNA methylation landscape of the human genome. Nature 500, 477–481 (2013).
Li, E. & Zhang, Y. DNA methylation in mammals. Cold Spring Harb. Perspect. Biol. 6, a019133 (2014).
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).
Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).
He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).
Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).
Ji, D., Lin, K., Song, J. & Wang, Y. Effects of Tet-induced oxidation products of 5-methylcytosine on Dnmt1- and DNMT3a-mediated cytosine methylation. Mol. Biosyst. 10, 1749–1752 (2014).
Hashimoto, H. et al. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 40, 4841–4849 (2012).
Valinluck, V. & Sowers, L. C. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 67, 946–950 (2007).
Wu, H. & Zhang, Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45–68 (2014).
Schön, A. et al. Analysis of an active deformylation mechanism of 5-formyl-deoxycytidine (fdC) in stem cells. Angew. Chem. Int. Ed. 59, 5591–5594 (2020).
Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).
Ficz, G. et al. FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency. Cell Stem Cell 13, 351–359 (2013).
Lee, H. J., Hore, T. A. & Reik, W. Reprogramming the methylome: erasing memory and creating diversity. Cell Stem Cell 14, 710–719 (2014).
Ginno, P. A. et al. A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity. Nat. Commun. 11, 2680 (2020).
Rulands, S. et al. Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Syst. 7, 63–76.e12 (2018).
Song, Y. et al. Dynamic enhancer DNA methylation as basis for transcriptional and cellular heterogeneity of ESCs. Mol. Cell 75, 905–920.e6 (2019).
Charlton, J. et al. TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers. Nat. Genet. 8, 819–827 (2020).
Spada, F. et al. Active turnover of genomic methylcytosine in pluripotent cells. Nat. Chem. Biol. https://doi.org/10.1038/s41589-020-0621-y (2020).
Chen, Z. & Zhang, Y. Role of mammalian DNA methyltransferases in development. Annu. Rev. Biochem. 89, 135–158 (2020).
Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cell 11, 805–814 (2006).
Dawlaty, M. M. et al. Loss of Tet enzymes compromises proper differentiation of embryonic stem cells. Dev. Cell 29, 102–111 (2014).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Dai, H. Q. et al. TET-mediated DNA demethylation controls gastrulation by regulating Lefty–Nodal signalling. Nature 538, 528–532 (2016).
Lei, H. et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195–3205 (1996).
Yamagata, Y. et al. Rapid turnover of DNA methylation in human cells. Epigenetics 7, 141–145 (2012).
Kalkan, T. et al. Tracking the embryonic stem cell transition from ground state pluripotency. Development 144, 1221–1234 (2017).
Morgani, S., Nichols, J. & Hadjantonakis, A. K. The many faces of pluripotency: in vitro adaptations of a continuum of in vivo states. BMC Dev. Biol. 17, 7 (2017).
Smith, A. Formative pluripotency: the executive phase in a developmental continuum. Development 144, 365–373 (2017).
Stelzer, Y., Shivalila, C. S., Soldner, F., Markoulaki, S. & Jaenisch, R. Tracing dynamic changes of DNA methylation at single-cell resolution. Cell 163, 218–229 (2015).
Guo, H. et al. Single-cell methylome landscapes of mouse embryonic stem cells and early embryos analyzed using reduced representation bisulfite sequencing. Genome Res. 23, 2126–2135 (2013).
Guo, H. et al. Profiling DNA methylome landscapes of mammalian cells with single-cell reduced-representation bisulfite sequencing. Nat. Protoc. 10, 645–659 (2015).
Bochtler, M., Kolano, A. & Xu, G. L. DNA demethylation pathways: additional players and regulators. Bioessays 39, 1–13 (2017).
Acebrón, J. A., Bonilla, L. L., Vicente, C. J. P., Ritort, F. & Spigler, R. The Kuramoto model: a simple paradigm for synchronization phenomena. Rev. Mod. Phys. 77, 137–185 (2005).
Strogatz, S. H., Abrams, D. M., McRobie, A., Eckhardt, B. & Ott, E. Crowd synchrony on the Millennium Bridge. Nature 438, 43–44 (2005).
Kangaspeska, S. et al. Transient cyclical methylation of promoter DNA. Nature 452, 112–115 (2008).
Métivier, R. et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452, 45–50 (2008).
Wang, K. Y., Chen, C. C. & Shen, C. K. J. Active DNA demethylation of the vertebrate genomes by DNA methyltransferases: deaminase, dehydroxymethylase or demethylase? Epigenomics 6, 353–363 (2014).
Chen, C. C., Wang, K. Y. & Shen, C. K. J. DNA 5-methylcytosine demethylation activities of the mammalian DNA methyltransferases. J. Biol. Chem. 288, 9084–9091 (2013).
Chen, C. C., Wang, K. Y. & Shen, C. K. J. The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J. Biol. Chem. 287, 33116–33121 (2012).
Shah, S. et al. Dynamics and spatial genomics of the nascent transcriptome by intron seqFISH. Cell 174, 363–376.e16 (2018).
Sneppen, K. & Ringrose, L. Theoretical analysis of Polycomb–Trithorax systems predicts that poised chromatin is bistable and not bivalent. Nat. Commun. 10, 2133 (2019).
Grosselin, K. et al. High-throughput single-cell ChIP–seq identifies heterogeneity of chromatin states in breast cancer. Nat. Genet. 51, 1060–1066 (2019).
Wang, Q. et al. CoBATCH for high-throughput single-cell epigenomic profiling. Mol. Cell 76, 206–216.e7 (2019).
Carter, B. et al. Mapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq). Nat. Commun. 10, 3747 (2019).
Harada, A. et al. A chromatin integration labelling method enables epigenomic profiling with lower input. Nat. Cell Biol. 21, 287–296 (2019).
Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).
Hu, L. et al. Crystal structure of TET2–DNA complex: insight into TET-mediated 5mC oxidation. Cell 155, 1545–1555 (2013).
Pastor, W. A., Aravind, L. & Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell Biol. 14, 341–356 (2013).
Williams, K. et al. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473, 343–349 (2011).
Xu, Y. et al. Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells. Mol. Cell 42, 451–464 (2011).
Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–394 (2011).
Hon, G. C. et al. 5mC oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol. Cell 56, 286–297 (2014).
Lu, F., Liu, Y., Jiang, L., Yamaguchi, S. & Zhang, Y. Role of Tet proteins in enhancer activity and telomere elongation. Genes. Dev. 28, 2103–2119 (2014).
Rasmussen, K. D. & Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes. Dev. 30, 733–750 (2016).
Nakagawa, T. et al. CRL4VprBP E3 ligase promotes monoubiquitylation and chromatin binding of TET dioxygenases. Mol. Cell 57, 247–260 (2015).
Zhang, Y. W. et al. Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol. Cell 65, 323–335 (2017).
Okashita, N. et al. PRDM14 promotes active DNA demethylation through the ten–eleven translocation (TET)-mediated base excision repair pathway in embryonic stem cells. Development 141, 269–280 (2014).
Costa, Y. et al. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495, 370–374 (2013).
Rebeiz, M. & Tsiantis, M. Enhancer evolution and the origins of morphological novelty. Curr. Opin. Genet. Dev. 45, 115–123 (2017).
Ramos, A. I. & Barolo, S. Low-affinity transcription factor binding sites shape morphogen responses and enhancer evolution. Philos. Trans. R. Soc. B Biol. Sci. 368, 20130018 (2013).
Farley, E. K. et al. Suboptimization of developmental enhancers. Science 350, 325–328 (2015).
Gu, T. et al. DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells. Genome Biol. 19, 88 (2018).
Otani, J. et al. Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX–DNMT3–DNMT3L domain. EMBO Rep. 10, 1235–1241 (2009).
Ooi, S. K. T. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007).
Rush, M. et al. Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 4, 404–414 (2009).
Li, H. et al. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J. Biol. Chem. 281, 19489–19500 (2006).
Hervouet, E., Peixoto, P., Delage-Mourroux, R., Boyer-Guittaut, M. & Cartron, P. F. Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma. Clin. Epigenetics 10, 17 (2018).
Brenner, C. et al. Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J. 24, 336–346 (2005).
Kriaucionis, S. & Heintz, N. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929–930 (2009).
Szulwach, K. E. et al. 5-hmC-Mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nat. Neurosci. 14, 1607–1616 (2011).
Rudenko, A. et al. Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. Neuron 79, 1109–1122 (2013).
Hahn, M. A. et al. Dynamics of 5-hydroxymethylcytosine and chromatin marks in mammalian neurogenesis. Cell Rep. 3, 291–300 (2013).
Izzo, F. et al. DNA methylation disruption reshapes the hematopoietic differentiation landscape. Nat. Genet. 52, 378–387 (2020).
Apostolou, E. & Hochedlinger, K. Chromatin dynamics during cellular reprogramming. Nature 502, 462–471 (2013).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Pawlak, M. & Jaenisch, R. De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state. Genes Dev. 25, 1035–1040 (2011).
Onder, T. T. et al. Chromatin-modifying enzymes as modulators of reprogramming. Nature 483, 598–602 (2012).
Doege, C. A. et al. Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Nature 488, 652–655 (2012).
Hu, X. et al. Tet and TDG mediate DNA demethylation essential for mesenchymal-to-epithelial transition in somatic cell reprogramming. Cell Stem Cell 14, 512–522 (2014).
Sardina, J. L. et al. Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell 23, 727–741.e9 (2018).
Ostrander, E. L. et al. Divergent effects of Dnmt3a and Tet2 mutations on hematopoietic progenitor cell fitness. Stem Cell Rep. 14, 551–560 (2020).
Clark, S. J. et al. ScNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9, 781 (2018).
Bachman, M. et al. 5-Formylcytosine can be a stable DNA modification in mammals. Nat. Chem. Biol. 11, 555–557 (2015).
Bachman, M. et al. 5-Hydroxymethylcytosine is a predominantly stable DNA modification. Nat. Chem. 6, 1049–1055 (2014).
Iurlaro, M. et al. In vivo genome-wide profiling reveals a tissue-specific role for 5-formylcytosine. Genome Biol. 17, 141 (2016).
Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017).
Yu, M. et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 149, 1368–1380 (2012).
Iurlaro, M. et al. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Genome Biol. 14, R119 (2013).
Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013).
Field, A. & Adelman, K. Evaluating enhancer function and transcription. Annu. Rev. Biochem. 89, 213–234 (2020).
Mohammed, H. et al. Single-cell landscape of transcriptional heterogeneity and cell fate decisions during mouse early gastrulation. Cell Rep. 20, 1215–1228 (2017).
Pujadas, E. & Feinberg, A. P. Regulated noise in the epigenetic landscape of development and disease. Cell 148, 1123–1131 (2012).
Holtzman, L. & Gersbach, C. A. Editing the epigenome: reshaping the genomic landscape. Annu. Rev. Genomics Hum. Genet. 19, 43–71 (2018).