Key Points
-
DNA methylation is highly correlated with the histone H3K9me mark in silenced genes from fungi to human.
-
DNA methylation and H3K9me marks crosstalk with each other through certain structural domains that specifically recognize methylated DNA and histones.
-
The fungi Neurospora crassa has a unidirectional regulation pathway from histone to DNA methylation.
-
Recent structural and functional studies have uncovered the complex cross regulatory network between DNA and histone methylation in the model plant Arabidopsis thaliana.
-
In mammals, multiple pathways are involved in both de novo and maintenance DNA methylation linking unmethylated H3K4, H3K9me and H3K36me to various targeting mechanisms.
Abstract
Methylation of DNA and of histone 3 at Lys 9 (H3K9) are highly correlated with gene silencing in eukaryotes from fungi to humans. Both of these epigenetic marks need to be established at specific regions of the genome and then maintained at these sites through cell division. Protein structural domains that specifically recognize methylated DNA and methylated histones are key for targeting enzymes that catalyse these marks to appropriate genome sites. Genetic, genomic, structural and biochemical data reveal connections between these two epigenetic marks, and these domains mediate much of the crosstalk.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Grewal, S. I. & Jia, S. Heterochromatin revisited. Nat. Rev. Genet. 8, 35–46 (2007).
Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).
Law, J. A. & Jacobsen, S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 11, 204–220 (2010).
Dhayalan, A. et al. The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J. Biol. Chem. 285, 26114–26120 (2010).
Hodges, E. et al. High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res. 19, 1593–1605 (2009).
Boulard, M., Edwards, J. R. & Bestor, T. H. FBXL10 protects Polycomb-bound genes from hypermethylation. Nat. Genet. 47, 479–485 (2015).
Saksouk, N. et al. Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation. Mol. Cell 56, 580–594 (2014).
Selker, E. U., Cambareri, E. B., Jensen, B. C. & Haack, K. R. Rearrangement of duplicated DNA in specialized cells of Neurospora. Cell 51, 741–752 (1987).
Selker, E. U. & Garrett, P. W. DNA sequence duplications trigger gene inactivation in Neurospora crassa. Proc. Natl Acad. Sci. USA 85, 6870–6874 (1988).
Selker, E. U. Premeiotic instability of repeated sequences in Neurospora crassa. Annu. Rev. Genet. 24, 579–613 (1990).
Cambareri, E. B., Jensen, B. C., Schabtach, E. & Selker, E. U. Repeat-induced G-C to A-T mutations in Neurospora. Science 244, 1571–1575 (1989).
Belden, W. J., Lewis, Z. A., Selker, E. U., Loros, J. J. & Dunlap, J. C. CHD1 remodels chromatin and influences transient DNA methylation at the clock gene frequency. PLoS Genet. 7, e1002166 (2011).
Dang, Y., Li, L., Guo, W., Xue, Z. & Liu, Y. Convergent transcription induces dynamic DNA methylation at disiRNA loci. PLoS Genet. 9, e1003761 (2013).
Selker, E. U., Fritz, D. Y. & Singer, M. J. Dense nonsymmetrical DNA methylation resulting from repeat-induced point mutation in Neurospora. Science 262, 1724–1728 (1993).
Selker, E. U. & Stevens, J. N. DNA methylation at asymmetric sites is associated with numerous transition mutations. Proc. Natl Acad. Sci. USA 82, 8114–8118 (1985).
Selker, E. U. et al. Induction and maintenance of nonsymmetrical DNA methylation in Neurospora. Proc. Natl Acad. Sci. USA 99 (Suppl. 4), 16485–16490 (2002).
Lewis, Z. A. et al. Relics of repeat-induced point mutation direct heterochromatin formation in Neurospora crassa. Genome Res. 19, 427–437 (2009).
Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001).
Tamaru, H. et al. Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat. Genet. 34, 75–79 (2003).
Lewis, Z. A. et al. DNA methylation and normal chromosome behavior in Neurospora depend on five components of a histone methyltransferase complex, DCDC. PLoS Genet. 6, e1001196 (2010).
Lewis, Z. A., Adhvaryu, K. K., Honda, S., Shiver, A. L. & Selker, E. U. Identification of DIM-7, a protein required to target the DIM-5 H3 methyltransferase to chromatin. Proc. Natl Acad. Sci. USA 107, 8310–8315 (2010).
Honda, S. et al. The DMM complex prevents spreading of DNA methylation from transposons to nearby genes in Neurospora crassa. Genes Dev. 24, 443–454 (2010).
Honda, S. et al. Heterochromatin protein 1 forms distinct complexes to direct histone deacetylation and DNA methylation. Nat. Struct. Mol. Biol. 19, 471–477 (2012).
Honda, S. & Selker, E. U. Direct interaction between DNA methyltransferase DIM-2 and HP1 is required for DNA methylation in Neurospora crassa. Mol. Cell. Biol. 28, 6044–6055 (2008).
Freitag, M., Hickey, P. C., Khlafallah, T. K., Read, N. D. & Selker, E. U. HP1 is essential for DNA methylation in Neurospora. Mol. Cell 13, 427–434 (2004).
Cokus, S. J. et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452, 215–219 (2008).
Lister, R. et al. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133, 523–536 (2008).
Zhang, X. et al. Genome-wide high-resolution mapping and functional analysis of DNA methylation in arabidopsis. Cell 126, 1189–1201 (2006).
Zhao, Z. & Shen, W. H. Plants contain a high number of proteins showing sequence similarity to the animal SUV39H family of histone methyltransferases. Ann. NY Acad. Sci. 1030, 661–669 (2004).
Cao, X. & Jacobsen, S. E. Role of the arabidopsis DRM methyltransferases in de novo DNA methylation and gene silencing. Curr. Biol. 12, 1138–1144 (2002).
Bartee, L., Malagnac, F. & Bender, J. Arabidopsis cmt3 chromomethylase mutations block non-CG methylation and silencing of an endogenous gene. Genes Dev. 15, 1753–1758 (2001).
Lindroth, A. M. et al. Requirement of CHROMOMETHYLASE3 for maintenance of CpXpG methylation. Science 292, 2077–2080 (2001).
Finnegan, E. J., Peacock, W. J. & Dennis, E. S. Reduced DNA methylation in Arabidopsis thaliana results in abnormal plant development. Proc. Natl Acad. Sci. USA 93, 8449–8454 (1996).
Ebbs, M. L. & Bender, J. Locus-specific control of DNA methylation by the Arabidopsis SUVH5 histone methyltransferase. Plant Cell 18, 1166–1176 (2006).
Bernatavichute, Y. V., Zhang, X., Cokus, S., Pellegrini, M. & Jacobsen, S. E. Genome-wide association of histone H3 lysine nine methylation with CHG DNA methylation in Arabidopsis thaliana. PloS ONE 3, e3156 (2008).
Johnson, L. M., Law, J. A., Khattar, A., Henderson, I. R. & Jacobsen, S. E. SRA-domain proteins required for DRM2-mediated de novo DNA methylation. PLoS Genet. 4, e1000280 (2008).
Johnson, L. M. et al. SRA- and SET-domain-containing proteins link RNA polymerase V occupancy to DNA methylation. Nature 507, 124–128 (2014).
Kuhlmann, M. & Mette, M. F. Developmentally non-redundant SET domain proteins SUVH2 and SUVH9 are required for transcriptional gene silencing in Arabidopsis thaliana. Plant Mol. Biol. 79, 623–633 (2012).
Liu, Z. W. et al. The SET domain proteins SUVH2 and SUVH9 are required for Pol V occupancy at RNA-directed DNA methylation loci. PLoS Genet. 10, e1003948 (2014).
Stroud, H. et al. Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis. Nat. Struct. Mol. Biol. 21, 64–72 (2014). This paper describes the tight links between non-CG methylation and both H3K9 methylation and siRNAs.
Du, J. et al. Dual binding of chromomethylase domains to H3K9me2-containing nucleosomes directs DNA methylation in plants. Cell 151, 167–180 (2012). This paper describes structural and functional insights underlying a dual-binding mode of histone-regulating DNA methyltransferase.
Jackson, J. P., Lindroth, A. M., Cao, X. & Jacobsen, S. E. Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416, 556–560 (2002).
Malagnac, F., Bartee, L. & Bender, J. An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J. 21, 6842–6852 (2002).
Tran, R. K. et al. Chromatin and siRNA pathways cooperate to maintain DNA methylation of small transposable elements in Arabidopsis. Genome Biol. 6, R90 (2005).
Soppe, W. J. et al. DNA methylation controls histone H3 lysine 9 methylation and heterochromatin assembly in Arabidopsis. EMBO J. 21, 6549–6559 (2002).
Mathieu, O., Probst, A. V. & Paszkowski, J. Distinct regulation of histone H3 methylation at lysines 27 and 9 by CpG methylation in Arabidopsis. EMBO J. 24, 2783–2791 (2005).
Tariq, M. et al. Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin. Proc. Natl Acad. Sci. USA 100, 8823–8827 (2003).
Johnson, L. M. et al. The SRA methyl-cytosine-binding domain links DNA and histone methylation. Curr. Biol. 17, 379–384 (2007).
Inagaki, S. et al. Autocatalytic differentiation of epigenetic modifications within the Arabidopsis genome. EMBO J. 29, 3496–3506 (2010).
Henikoff, S. & Comai, L. A. DNA methyltransferase homolog with a chromodomain exists in multiple polymorphic forms in Arabidopsis. Genetics 149, 307–318 (1998).
Finnegan, E. J. & Kovac, K. A. Plant DNA methyltransferases. Plant Mol. Biol. 43, 189–201 (2000).
Papa, C. M., Springer, N. M., Muszynski, M. G., Meeley, R. & Kaeppler, S. M. Maize chromomethylase Zea methyltransferase2 is required for CpNpG methylation. Plant Cell 13, 1919–1928 (2001).
Patel, D. J. & Wang, Z. Readout of epigenetic modifications. Annu. Rev. Biochem. 82, 81–118 (2013).
Du, J. et al. Mechanism of DNA methylation-directed histone methylation by KRYPTONITE. Mol. Cell 55, 495–504 (2014). This paper outlines the structural basis underlying methylated DNA-mediated regulation of lysine methylation by a histone lysine methyltransferase.
Zemach, A. et al. The Arabidopsis nucleosome remodeler DDM1 allows DNA methyltransferases to access H1-containing heterochromatin. Cell 153, 193–205 (2013).
Stroud, H., Greenberg, M. V., Feng, S., Bernatavichute, Y. V. & Jacobsen, S. E. Comprehensive analysis of silencing mutants reveals complex regulation of the Arabidopsis methylome. Cell 152, 352–364 (2013).
Matzke, M. A. & Mosher, R. A. RNA-directed DNA methylation: an epigenetic pathway of increasing complexity. Nat. Rev. Genet. 15, 394–408 (2014).
Pontier, D. et al. Reinforcement of silencing at transposons and highly repeated sequences requires the concerted action of two distinct RNA polymerases IV in Arabidopsis. Genes Dev. 19, 2030–2040 (2005).
Law, J. A., Vashisht, A. A., Wohlschlegel, J. A. & Jacobsen, S. E. SHH1, a homeodomain protein required for DNA methylation, as well as RDR2, RDM4, and chromatin remodeling factors, associate with RNA polymerase IV. PLoS Genet. 7, e1002195 (2011).
Law, J. A. et al. Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1. Nature 498, 385–389 (2013). This paper elucidated the structure-function links between RdDM and the H3K9me mark.
Zhang, H. et al. DTF1 is a core component of RNA-directed DNA methylation and may assist in the recruitment of Pol IV. Proc. Natl Acad. Sci. USA 110, 8290–8295 (2013).
Liu, J. et al. An atypical component of RNA-directed DNA methylation machinery has both DNA methylation-dependent and -independent roles in locus-specific transcriptional gene silencing. Cell Res. 21, 1691–1700 (2011).
Law, J. A. et al. A protein complex required for polymerase V transcripts and RNA- directed DNA methylation in Arabidopsis. Curr. Biol. 20, 951–956 (2010).
Pikaard, C. S., Haag, J. R., Ream, T. & Wierzbicki, A. T. Roles of RNA polymerase IV in gene silencing. Trends Plant Sci. 13, 390–397 (2008).
Wierzbicki, A. T., Ream, T. S., Haag, J. R. & Pikaard, C. S. RNA polymerase V transcription guides ARGONAUTE4 to chromatin. Nat. Genet. 41, 630–634 (2009).
Zhong, X. et al. Molecular mechanism of action of plant DRM de novo DNA methyltransferases. Cell 157, 1050–1060 (2014).
Naumann, K. et al. Pivotal role of AtSUVH2 in heterochromatic histone methylation and gene silencing in Arabidopsis. EMBO J. 24, 1418–1429 (2005).
Deleris, A. et al. Involvement of a Jumonji-C domain-containing histone demethylase in DRM2-mediated maintenance of DNA methylation. EMBO Rep. 11, 950–955 (2010).
Searle, I. R., Pontes, O., Melnyk, C. W., Smith, L. M. & Baulcombe, D. C. JMJ14, a JmjC domain protein, is required for RNA silencing and cell-to-cell movement of an RNA silencing signal in Arabidopsis. Genes Dev. 24, 986–991 (2010).
Zhang, Y. et al. 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 (2010).
Greenberg, M. V. et al. Interplay between active chromatin marks and RNA-directed DNA methylation in Arabidopsis thaliana. PLoS Genet. 9, e1003946 (2013).
Aufsatz, W., Mette, M. F., van der Winden, J., Matzke, M. & Matzke, A. J. HDA6, a putative histone deacetylase needed to enhance DNA methylation induced by double-stranded RNA. EMBO J. 21, 6832–6841 (2002).
Earley, K. et al. Erasure of histone acetylation by Arabidopsis HDA6 mediates large-scale gene silencing in nucleolar dominance. Genes Dev. 20, 1283–1293 (2006).
Probst, A. V. et al. Arabidopsis histone deacetylase HDA6 is required for maintenance of transcriptional gene silencing and determines nuclear organization of rDNA repeats. Plant Cell 16, 1021–1034 (2004).
Aufsatz, W., Stoiber, T., Rakic, B. & Naumann, K. Arabidopsis histone deacetylase 6: a green link to RNA silencing. Oncogene 26, 5477–5488 (2007).
Blevins, T. et al. A two-step process for epigenetic inheritance in Arabidopsis. Mol. Cell 54, 30–42 (2014).
Kankel, M. W. et al. Arabidopsis MET1 cytosine methyltransferase mutants. Genetics 163, 1109–1122 (2003).
Woo, H. R., Pontes, O., Pikaard, C. S. & Richards, E. J. VIM1, a methylcytosine-binding protein required for centromeric heterochromatinization. Genes Dev. 21, 267–277 (2007).
Woo, H. R., Dittmer, T. A. & Richards, E. J. Three SRA-domain methylcytosine-binding proteins cooperate to maintain global CpG methylation and epigenetic silencing in Arabidopsis. PLoS Genet. 4, e1000156 (2008).
Kraft, E., Bostick, M., Jacobsen, S. E. & Callis, J. ORTH/VIM proteins that regulate DNA methylation are functional ubiquitin E3 ligases. Plant J. 56, 704–715 (2008).
Rigal, M., Kevei, Z., Pelissier, T. & Mathieu, O. DNA methylation in an intron of the IBM1 histone demethylase gene stabilizes chromatin modification patterns. EMBO J. 31, 2981–2993 (2012).
Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).
Varley, K. E. et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res. 23, 555–567 (2013).
Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).
Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).
Guenatri, M., Bailly, D., Maison, C. & Almouzni, G. Mouse centric and pericentric satellite repeats form distinct functional heterochromatin. J. Cell Biol. 166, 493–505 (2004).
Robertson, K. D. & Wolffe, A. P. DNA methylation in health and disease. Nat. Rev. Genet. 1, 11–19 (2000).
Cheng, X. Structural and functional coordination of DNA and histone methylation. Cold Spring Harb. Perspect. Biol. 6, a018747 (2014).
Arand, J. et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 8, e1002750 (2012).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).
Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).
Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G. & Rauscher, F. J. 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).
Shinkai, Y. & Tachibana, M. H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev. 25, 781–788 (2011).
Peters, A. H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).
Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6, 838–849 (2005).
Minkovsky, A. et al. The Mbd1–Atf7ip–Setdb1 pathway contributes to the maintenance of X chromosome inactivation. Epigenetics Chromatin 7, 12 (2014).
Karimi, M. M. et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell 8, 676–687 (2011).
Firestein, R., Cui, X., Huie, P. & Cleary, M. L. Set domain-dependent regulation of transcriptional silencing and growth control by SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9. Mol. Cell. Biol. 20, 4900–4909 (2000).
Collins, R. E. et al. The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules. Nat. Struct. Mol. Biol. 15, 245–250 (2008).
Fritsch, L. et al. A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex. Mol. Cell 37, 46–56 (2010).
Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).
Ikegami, K. et al. Genome-wide and locus-specific DNA hypomethylation in G9a deficient mouse embryonic stem cells. Genes Cells 12, 1–11 (2007).
Dong, K. B. et al. DNA methylation in ES cells requires the lysine methyltransferase G9a but not its catalytic activity. EMBO J. 27, 2691–2701 (2008).
Leung, D. et al. Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1. Proc. Natl Acad. Sci. USA 111, 6690–6695 (2014).
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 Cells 11, 805–814 (2006).
Matsui, T. et al. Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464, 927–931 (2010).
Bachman, K. E. et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89–95 (2003).
Espada, J. et al. Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern. J. Biol. Chem. 279, 371 75–37184 (2004).
Nguyen, C. T. et al. Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2′-deoxycytidine. Cancer Res. 62, 6456–6461 (2002).
Rose, N. R. & Klose, R. J. Understanding the relationship between DNA methylation and histone lysine methylation. Biochim. Biophys. Acta 1839, 1362–1372 (2014).
Smith, Z. D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).
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. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007). This paper reports on structural evidence that a histone modification regulated DNA methyltransferase activity.
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).
Iwase, S. et al. ATRX links atypical histone methylation recognition mechanisms to human mental retardation syndrome. Nat. Struct. Mol. Biol. 18, 769–776 (2011).
Eustermann, S. et al. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. Nat. Struct. Mol. Biol. 18, 777–782 (2011).
Ciccone, D. N. et al. KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461, 415–418 (2009).
Epsztejn-Litman, S. et al. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes. Nat. Struct. Mol. Biol. 15, 1176–1183 (2008).
Kokura, K., Sun, L., Bedford, M. T. & Fang, J. Methyl-H3K9-binding protein MPP8 mediates E-cadherin gene silencing and promotes tumour cell motility and invasion. EMBO J. 29, 3673–3687 (2010).
Chang, Y. et al. MPP8 mediates the interactions between DNA methyltransferase Dnmt3a and H3K9 methyltransferase GLP/G9a. Nat. Commun. 2, 533 (2011).
Okada, T. et al. CENP-B controls centromere formation depending on the chromatin context. Cell 131, 1287–1300 (2007).
Ando, S., Yang, H., Nozaki, N., Okazaki, T. & Yoda, K. CENP-A, -B, and -C chromatin complex that contains the I-type α-satellite array constitutes the prekinetochore in HeLa cells. Mol. Cell. Biol. 22, 2229–2241 (2002).
Gopalakrishnan, S., Sullivan, B. A., Trazzi, S., Della Valle, G. & Robertson, K. D. DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions. Hum. Mol. Genet. 18, 3178–3193 (2009).
Fuks, F., Hurd, P. J., Deplus, R. & Kouzarides, T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res. 31, 2305–2312 (2003).
Smallwood, A., Esteve, P. O., Pradhan, S. & Carey, M. Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes Dev. 21, 1169–1178 (2007).
Muramatsu, D., Singh, P. B., Kimura, H., Tachibana, M. & Shinkai, Y. Pericentric heterochromatin generated by HP1 protein interaction-defective histone methyltransferase Suv39h1. J. Biol. Chem. 288, 25285–25296 (2013). This paper shows that the SUV39H–HP1 interaction is dispensable for pericentric H3K9me3 and DNA methylation, but is necessary for HP1 recruitment and completion of heterochromatin formation.
Krouwels, I. M. et al. A glue for heterochromatin maintenance: stable SUV39H1 binding to heterochromatin is reinforced by the SET domain. J. Cell Biol. 170, 537–549 (2005).
Rowe, H. M. et al. De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET. Development 140, 519–529 (2013).
Wolf, D. & Goff, S. P. Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458, 1201–1204 (2009).
Jacobs, F. M. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014).
Leung, D. C. et al. Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment, but not the maintenance, of proviral silencing. Proc. Natl Acad. Sci. USA 108, 5718–5723 (2011).
Rowe, H. M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010).
Leung, D. C. & Lorincz, M. C. Silencing of endogenous retroviruses: when and why do histone marks predominate? Trends Biochem. Sci. 37, 127–133 (2012).
Jin, B. et al. Linking DNA methyltransferases to epigenetic marks and nucleosome structure genome-wide in human tumor cells. Cell Rep. 2, 1411–1424 (2012).
Morselli, M. et al. In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. eLife 4, e06205 (2015).
Bell, O. et al. Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila. EMBO J. 26, 4974–4984 (2007).
Jia, D., Jurkowska, R. Z., Zhang, X., Jeltsch, A. & Cheng, X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449, 248–251 (2007).
Zhang, Y. et al. DNA methylation analysis of chromosome 21 gene promoters at single base pair and single allele resolution. PLoS Genet. 5, e1000438 (2009).
Li, B. Z. et al. Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res. 21, 1172–1181 (2011).
Guo, X. et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517, 640–644 (2015). This paper shows a structure-based mechanism underlying histone-based allosteric regulation of de novo DNA methyltransferase activity.
Esteve, P. O. et al. Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes Dev. 20, 3089–3103 (2006).
Song, J., Rechkoblit, O., Bestor, T. H. & Patel, D. J. Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331, 1036–1040 (2011).
Song, J., Teplova, M., Ishibe-Murakami, S. & Patel, D. J. Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335, 709–712 (2012). This paper, with reference 144, defines the structural basis for autoinhibitory and active mechanisms for regulation of DNMT1 activity.
Takeshita, K. et al. Structural insight into maintenance methylation by mouse DNA methyltransferase 1 (Dnmt1). Proc. Natl Acad. Sci. USA 108, 9055–9059 (2011).
Yang, N. & Xu, R. M. Structure and function of the BAH domain in chromatin biology. Crit. Rev. Biochem. Mol. Biol. 48, 211–221 (2013).
Kuo, A. J. et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier–Gorlin syndrome. Nature 484, 115–119 (2012).
Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760–1764 (2007).
Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007).
Karagianni, P., Amazit, L., Qin, J. & Wong, J. ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Mol. Cell. Biol. 28, 705–717 (2008).
Nady, N. et al. Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J. Biol. Chem. 286, 24300–24311 (2011).
Rajakumara, E. et al. PHD finger recognition of unmodified histone H3R2 links UHRF1 to regulation of euchromatic gene expression. Mol. Cell 43, 275–284 (2011).
Hu, L., Li, Z., Wang, P., Lin, Y. & Xu, Y. Crystal structure of PHD domain of UHRF1 and insights into recognition of unmodified histone H3 arginine residue 2. Cell Res. 21, 1374–1378 (2011).
Wang, C. et al. Structural basis for site-specific reading of unmodified R2 of histone H3 tail by UHRF1 PHD finger. Cell Res. 21, 1379–1382 (2011).
Cheng, J. et al. Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein. J. Biol. Chem. 288, 1329–1339 (2013).
Arita, K. et al. Recognition of modification status on a histone H3 tail by linked histone reader modules of the epigenetic regulator UHRF1. Proc. Natl Acad. Sci. USA 109, 12950–12955 (2012). References 157 and 156 report on the mechanism of histone recognition by UHRF1, thereby linking H3K9me3 mark to CG methylation maintanance.
Rothbart, S. B. et al. Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. Genes Dev. 27, 1288–1298 (2013).
Gelato, K. A. et al. Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol. Cell 54, 905–919 (2014).
Rottach, A. et al. The multi-domain protein Np95 connects DNA methylation and histone modification. Nucleic Acids Res. 38, 1796–1804 (2010).
Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y. & Shirakawa, M. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455, 818–821 (2008).
Avvakumov, G. V. et al. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455, 822–825 (2008).
Hashimoto, H. et al. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455, 826–829 (2008). The above three papers describe the structural basis underlying recognition of hemimethylated DNA by UHRF1, thereby linking UHRF1 to CG methylation maintenance.
Felle, M. et al. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1. Nucleic Acids Res. 39, 8355–8365 (2011).
Berkyurek, A. C. et al. The DNA methyltransferase Dnmt1 directly interacts with the SET and RING finger-associated (SRA) domain of the multifunctional protein Uhrf1 to facilitate accession of the catalytic center to hemi-methylated DNA. J. Biol. Chem. 289, 379–386 (2014).
Bashtrykov, P., Jankevicius, G., Jurkowska, R. Z., Ragozin, S. & Jeltsch, A. The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism. J. Biol. Chem. 289, 4106–4115 (2014).
Achour, M. et al. The interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 is involved in the regulation of VEGF gene expression. Oncogene 27, 2187–2197 (2008).
Citterio, E. et al. Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Mol. Cell. Biol. 24, 2526–2535 (2004).
Nishiyama, A. et al. Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 502, 249–253 (2013).
Leonhardt, H., Page, A. W., Weier, H. U. & Bestor, T. H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865–873 (1992).
Acknowledgements
The authors thank W. Pastor and E. Selker for helpful comments on the manuscript. This work was supported by the Chinese Academy of Sciences (to J.D.), NIH grant GM60398 (to S.E.J.), and LLSCOR Program Project and STARR Foundation grants (to D.J.P.). S.E.J. is an investigator of the Howard Hughes Medical Institute.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Symmetrical sequences
-
DNA fragments that display the same sequence on both DNA strands.
- Asymmetrical sequence
-
A sequence that is only present on one strand of the DNA.
- Readers
-
Proteins and domains capable of binding to a specific epigenetic mark to recruit certain proteins to the target epigenetic mark.
- Chromodomains
-
A type of reader module that targets histone lysine methylation marks.
- Bromo adjacent homology domains
-
(BAH domains). Another type of reader module that targets histone lysine methylation marks.
- Hemimethylated sites
-
DNA sequences that are methylated on only one of the two complementary DNA strands.
- Agrobacterium tumefaciens-mediated transformation
-
The process of experimentally inserting foreign DNA in the genome of a plant via infiltration with Agrobacterium tumefaciens.
- Isothermal Titration Calorimetry
-
(ITC). A biophysical technique that quantifies the solution interaction features by measuring the reaction thermodynamic changes.
- Epiallele
-
An allele that differs in its epigenetic marks, not in its DNA sequence.
- Major satellites
-
Refers to the 234 bp repeat sequence found in the pericentromeric region in mice.
- Minor satellites
-
Refers to the 120 bp repeat sequences found in the centromeric region in mice.
- Retroviruses
-
RNA viruses that use reverse transcriptase to convert their genome into DNA, which is then integrated into the host genome.
- Repetitive element
-
A sequence that is found in multiple copies in the genome. Examples are telomeric repeats, transposable elements, and centromeric repeats.
- Inactive X chromosome
-
One of the two X chromosomes in females is inactivated to prevent overexpression of X gene products in females compared to males. This silencing is done through formation of heterochromatin.
- Primordial germ cell
-
A Cell that gives rise to both spermatozoa and oocytes.
- Retroelements
-
Transposable elements that move via the transcription of an RNA intermediate.
Rights and permissions
About this article
Cite this article
Du, J., Johnson, L., Jacobsen, S. et al. DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol 16, 519–532 (2015). https://doi.org/10.1038/nrm4043
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm4043
