Several Authors have reported that histone methylation interacts with DNA methylation creating a self-propagating epigenetic cycle for long-term transcriptional repression of methylated genome compartments. This phenomenon, observed in plant and vertebrate genomes, does not appear to hold true in invertebrates. In particular, both structural and functional evidences suggest that, in invertebrates, DNA methylation and histone methylation do not interact, thus inhibiting the intimate pas de deux observed in other eukaryotes

Borsatti, Federica

Mandrioli, Mauro

Several Authors have reported that histone methylation interacts with DNA methylation creating aself-propagating epigenetic cycle for long-term transcriptional repression of methylated genomecompartments. This phenomenon, observed in plant and vertebrate genomes, does not appear to holdtrue in invertebrates. In particular, both structural and functional evidences suggest that, ininvertebrates, DNA methylation and histone methylation do not interact, thus inhibiting the intimate pasde deux observed in other eukaryotes

M Mandrioli

F Borsatti

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  159ISJ 2: 159-161, 2005               ISSN 1824-307X   Visions and Perspectives    Histone methylation and DNA methylation: a missed pas de deux in invertebrates?   M Mandrioli, F Borsatti  Department of Animal Biology, University of Modena and Reggio Emilia, Modena, Italy   Accepted December 27, 2005   Abstract Several Authors have reported that histone methylation interacts with DNA methylation creating a self-propagating epigenetic cycle for long-term transcriptional repression of methylated genome compartments. This phenomenon, observed in plant and vertebrate genomes, does not appear to hold true in invertebrates. In particular, both structural and functional evidences suggest that, in invertebrates, DNA methylation and histone methylation do not interact, thus inhibiting the intimate pas de deux observed in other eukaryotes.  Key words: epigenetics; histone methylation; DNA methylation; invertebrate genome     Studies on organisms ranging from yeast to vertebrates have indicated that histones and their post-translational modifications play an evolutionary conserved pivotal role in the assembly of chromatin. In particular, the presence of different covalent modifications of histones has led to the definition of the “histone code,” i.e. a code that is deciphered by chromosomal proteins in order to regulate gene expression using specific modifications of chromatin architecture. Among the plethora of modifications, histone methylation, to a greater extent than any other process (such as acetylation, phosphorylation and ubiquitination), has shown the capacity to regulate fundamental processes like gene transcription and DNA repair (Bannister and Kouzarides, 2005).  Histone methylation on either lysine or arginine residues induces alterations in chromatin architecture   Corresponding Author: Mauro Mandrioli Department of Animal Biology, University of Modena and Reggio Emilia, via Campi 213/D, 41100 Modena, Italy E-mail: mandrioli.mauro@unimore.it  List of abbreviations: HP1: heterochromatin protein 1; MeCP2: methyl CpG binding protein; Dnmt: DNA methyltransferase; PHD: plant homeo-domain; HDAC: histone deactylase  However, this result is not due to the methyl group itself (which does not neutralize lysine or arginine charge), but to the recruitment of silencing/regulatory proteins that bind methylated histones (Bannister and Kouzarides, 2005). Among these proteins, HP1 is an evolutionary conserved partner of histone methylase acting in synergy with histone methylation to silence chromatin. Finally, histone methylation interacts in plants and vertebrates with DNA methylation creating a self-propagating epigenetic cycle for long-term transcriptional repression of methylated genome compartments (Fuks et al., 2003). Given the presence of the same histone and DNA modifications at silenced domains in different eukaryotes, several Authors have hypothesized the existence of an evolutionary conserved interaction between histone methylation and DNA methylation (Fuks et al., 2003, Bannister and Kouzarides, 2005). This hypothesis is strengthened by data reporting that DNA methylation is associated, in plants and vertebrates, with gene silencing or to the permanent lock of already silenced genes (Fig 1).  Viewed as a whole, the most recent findings seem to suggest that at the beginning DNA methyltransferases would add a methyl group to DNA, only on chromatin that is methylated at lysine 9 of the H3  histone,  and bind HP1 (Fuks et al., 2003). The   160  Fig 1. Recent findings in Neurospora, Arabidopsis thaliana and mammals suggested that DNA methylation and histone methylation act together in chromatin silencing. In the initial phase, the Dnmts add methyl groups to DNA only on chromatin that  is methylated at lysine 9 and bind HP1. The direct physical link identified here between the Dnmts and the HMT–HP1 system would make sure that the methylation status at histone H3 directly influences DNA methylation patterns. In the second step, the generation of methylated DNA by the Dnmts would allow DNA binding of MBP, which in turn associates and favours histone methylation at lysine 9 of H3 histones. This sequential process of coupling DNA with histone methylation is attractive because it would suggest that DNA methylation may also feed back to facilitate histone methylation, thereby reinforcing the two modes of epigenetic silencing and creating a self-propagating epigenetic cycle for long-term transcriptional repression. Dnmt: DNA methyltransferase; HP1: heterochromatin protein 1; HMT: histone methyltransferase; H3K9: methylation of histone H3 at lysine 9; MBP: methyl-binding proteins.      Fig 2. Insect Dnmt2 lacks the N-terminal domain, present in Dnmt1 and Dnmt3, that is responsible for DNA methyltransferase interactions with numerous other proteins (A). The absence of the N-terminal domain in Dnmt2 could prevent the coupling of Dnmt2-mediated DNA methylation with histone methylation. These two epigenetic tools could be targeted to different genome compartments where they could play entirely different roles. This hypothesis is supported by data reporting that DNA methylation was involved in gene expression instead of gene silencing at euchromatic compartments of genome (B). These data suggest, therefore, the absence of a cross talk between DNA and histone methylation in insects. Dnmt: DNA methyltransferase.   161direct physical link between histone methylase and HP1 would ensure that the histone methylation status directly influences the DNA methylation pattern. In the second step, the generation of methylated CpG dinucleotides enables the binding of methyl-binding proteins (such as MeCP2), which in turn favour histone methylation so that DNA methylation may feed back to facilitate histone methylation leading to a silent state of chromatin (Fuks et al., 2003, Bannister and Kouzarides, 2005). However, several data reported in invertebrates (Field et al., 2004; Marhold et al., 2004; Borsatti et al., 2004; Borsatti and Mandrioli, 2004) argue against an evolutionary conserved function of DNA methylation and against the interaction between histone methylation and DNA methylation. In particular, the absence of cooperation between histone methylation and DNA methylation in invertebrates can be suggested in the light of data reporting the presence of a unique DNA methyltransferase lacking the typical domain involved in such an interaction and, most of all, in view of the different functions played by DNA methylation in invertebrates in comparison with plants and vertebrates. The insects Drosophila melanogaster, Bombyx mori, Apis mellifera and Anopheles gambiae possess a unique gene coding for DNA methyltransferases (and in particular for Dnmt2-like enzymes) that is responsible for DNA methylation (Marhold et al., 2004; Borsatti and Mandrioli, 2004). As opposed to the typical eukaryotic DNA methyltransferases, Dnmt2 lacks the N-terminal domain that is responsible for DNA methyltransferase interactions with numerous other proteins inhibiting the coupling of Dnmt2-mediated DNA methylation with histone methylation in insects. In particular, the typical eukaryotic DNA methyltransferase presents a C-terminal region, referred to as the catalytic domain, and a N-terminal region acting as a regulatory domain (Margot et al., 2000). The N-terminal domain presents different structural motifs (such as the PHD domain) that are responsible for DNA methyltransferase interactions with numerous other proteins. In this connection, several Authors have assessed that Dnmt1 and Dnmt3 interact with HP1 and HDAC through their N-terminal domains (Fuks et al., 2003). The hypothesis of a missed interaction of DNA methylation with other epigenetic tools is supported by the role that DNA methylation plays in insects, where experimental results have revealed that methylated genes are actively transcribed indicating the absence of the DNA methylation/gene silencing correlation (Field et al., 2004; Marhold et al., 2004; Borsatti et al., 2004; Borsatti and Mandrioli, 2004). In particular, in the insects Mamestra brassicae, Myzus persicae and Planococcus citri it has been described that several genes are actively transcribed even if methylated and that DNA methylation is essential to ensure gene expression (Field et al., 2004; Marhold et al., 2004; Borsatti et al., 2004; Borsatti and Mandrioli, 2004). Interestingly, insects are not the unique biological models where methylation is not involved in gene silencing, since similar results have been obtained in other invertebrates, such as the sea urchin Strongylocentrus purpuratus, the sea squirt Ciona intestinalis and the amphioxus Branchiostoma lanceolatum (Tweedie et al., 1997; Simmen et al., 1999).  The present analysis indicates, therefore, that even if histone methylation and DNA methylation mechanisms are both present in vertebrates and invertebrates, only histone methylation plays an evolutionary conserved role in gene silencing, whereas DNA methylation carries out different functions in different taxa. All the evidences produced here (both at structural and functional level) suggest that, in invertebrates, DNA methylation and histone methylation are targeted to different genomic compartments, where they have different and opposite effects (Fig 2). In invertebrates we therefore observe a loss of interaction between these two epigenetic tools thus inhibiting the realization of the intimate pas de deux observed in other eukaryotes.   Acknowledgements This work was supported by a grant of the University of Modena and Reggio Emilia (Italy).   References Bannister AJ, Kouzarides T. Reversing histone methylation. Nature 436: 1103-1106, 2005. Cowell IG, Aucott R, Mahadevaiah SK, et al. Heterochromatin, HP1 and methylation at lysine 9 of histone H3 in animals. Chromosoma 111: 22-36, 2002.   Kourmouli N, Jeppesen P, Mahadevhaiah S, et al. Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J. Cell Sci. 117: 2491-2501, 2004. Fuks F, Hurd PJ, Deplus R, Kouzarides T. The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucl. Acids Res. 31: 2305-2312, 2003. Field LM, Lyko F, Mandrioli M, Prantera G. DNA methylation in insects. Insect Mol. Biol. 13: 109-117, 2004. Marhold J, Rothe N, Pauli A, Mund C, Kuehle K, Lyko F. Conservation of DNA methylation in dipteran insects. Insect Mol. Biol. 13: 117-123, 2004. Borsatti F, Casarini L, Mandrioli M. Analysis of the expression pattern of the defensin gene in the lepidopteran Mamestra brassicae. Inv. Surv. J. 1: 34-37, 2004. Borsatti F, Mandrioli M. The structure of insect DNA methyltransferase 2 (Dnmt2) DNA binding domain is responsible for the non-CpG methylation in insect genomes. Caryologia 57: 305-311, 2004. Margot JB, Aguirre-Arteta AM, Di Giacco BV, et al. Structure and function of the mouse DNA methyltransferase gene: Dnmt1 shows a tripartite structure. J. Mol. Biol. 297: 293-300, 2000. Tweedie S, Charlton J, Clark V, Bird A. Methylation of genomes and genes at the invertebrate-vertebrate boundary. Mol. Cell. Biol. 17: 1469-1475, 1997. Simmen MW, Leitgeb S, Charlton J, et al. Non-methylated transposable elements and methylates genes in a chordate genome. Science 283: 1164-1167,1999. 

Histone methylation and DNA methylation: a missed pas de deux in invertebrates?

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