The Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation

Abstract

DNA methylation plays an important role in mammalian development and correlates with chromatinassociated gene silencing. The recruitment of MeCP2 to methylated CpG dinucleotides represents a major mechanism by which DNA methylation can repress transcription. MeCP2 silences gene expression partly by recruiting histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MeCP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys 9 of histone H3. Two characterized repression domains of MeCP2 are involved in tethering the histone methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys 9 H3 methylation to the H19 gene, whose activity it represses. We show that the presence of MeCP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys 9 methylation. Our data provide evidence that MeCP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA methylation and histone methylation.Methylation of cytosines is essential for mammalian development and is associated with gene silencing (1). DNA methylation represses genes partly by recruitment of methyl-CpGbinding domain proteins, which selectively recognize methylated CpG dinucleotides. MeCP2 is the founder member of the methyl-CpG-binding domain proteins, which consists of a single polypeptide that contains a methyl-CpG-binding domain and a transcriptional repression domain. MeCP2 is capable of binding to a single symmetrically methylated CpG both in naked DNA and within chromatin (2, 3).It is now well established that MeCP2 silences transcription by recruiting the histone deacetylase (HDAC) 1 repressive machinery, which removes acetyl groups from histones resulting in gene silencing (4,5). However, the inhibition of histone deacetylase activity using drugs such as Trichostatin A only partially relieves MeCP2-mediated transcriptional repression. This partial relief indicates that additional mechanisms of repression by MeCP2 likely exist aside from the recruitment of histone deacetylase.Beside histone deacetylation, histone methylation is emerging as another key post-translational modification of histones and represents an important epigenetic mechanism for the organization of chromatin structure and the regulation of gene expression. In particular, methylation at lysine 9 of histone H3 is associated with gene silencing, and several enzymes that catalyze the addition of methyl groups to lysine 9 have recently been identified (6). Interestingly, recent data have shown that the retinoblastoma protein represses transcription through the recruitment of HDAC activity, but in a second step it recruits histone methylation activity specific for lysine 9 of histone H3 (7). By analogy to retinoblastoma, we considered in the present work whether MeCP2-mediated repression might also include, besides histone deacetylation, a second stage involving histone methylatio...

The social environment and the epigenome

“…In humans and mice mutations in the SWI-SNF proteins, which are involved in chromatin remodeling, result in defects in DNA methylation. A growing list of histone modifying enzymes interact with DNMT1, such as HDAC1 and HDAC2, the histone methyltransferases SUV3-9 and EZH2, a member of the multiprotein Polycomb complex PRC2, which methylates H3 histone at the K27 residue [Fuks et al, 2000[Fuks et al, , 2003bRountree et al, 2000;Vire et al, 2006]. DNMT3a was recently also shown to interact with EZH2 which targets the DNA methylation-histone modification multiprotein complexes to specific sequences in DNA [Vire et al, 2006].…”

Epigenetic Up-Regulation of Leukemia Inhibitory Factor (LIF) Gene During the Progression to Breast Cancer

“…This epigenetic activation involves the reversal of inactive epigenetic marks including histone deacetylation by histone acetylation and DNA methylation by DNA hypomethylation. The epigenetic interplay between DNA methylation and inactive histone methylation provides evidence that MeCP2 associates with histone H3 Lys9 methyltransferase and may deliver this inactive mark to a DNA methylated gene (Fuks et al, 2003b). In addition, the interplay between DNA methylation and histone H3-Lys27-methylation was suggested in the recent report that demonstrated epigenetic analysis of the invasion promoting MMPs in cancer cells (Chernov et al, 2009).…”

“…DNA methylation has been recently linked to methylation of Lys9 of histone H3, which is a histone mark for transcriptional repression. Histone methylation can direct DNA methylation (Fuks et al, 2003a;2003b).…”

Epigenetics in development

“…Second, methyl-CpG binding domain proteins (MBPs) can reinforce silencing by recruiting corepressor complexes that harbor histone deacetylases (HDACs) or histone methyltransferases (HMTs). MBP-associated HMTs fuel a positive feedback loop between DNA methylation and another epigenetic silencing mark, methylated lysine 9 on histone 3 (H3K9; Fujita et al, 2003;Fuks et al, 2003).…”