Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation

Abstract

Methylation of DNA at the dinucleotide CpG is essential for mammalian development and is correlated with stable transcriptional silencing. This transcriptional silencing has recently been linked at a molecular level to histone deacetylation through the demonstration of a physical association between histone deacetylases and the methyl CpG-binding protein MeCP2 (refs 4,5). We previously purified a histone deacetylase complex from Xenopus laevis egg extracts that consists of six subunits, including an Rpd3-like deacetylase, the RbA p48/p46 histone-binding protein and the nucleosome-stimulated ATPase Mi-2 (ref. 6). Similar species were subsequently isolated from human cell lines, implying functional conservation across evolution. This complex represents the most abundant form of deacetylase in amphibian eggs and cultured mammalian cells. Here we identify the remaining three subunits of this enzyme complex. One of them binds specifically to methylated DNA in vitro and molecular cloning reveals a similarity to a known methyl CpG-binding protein. Our data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing.

Dynamic and reversibility of heterochromatic gene silencing in human disease

“…The methyl CpG binding proteins exert their function as transcriptional repressors via chromatin remodeling. These proteins are often part of larger repressor complexes as NuRD, NoRC, mSin3A and SWI-SNF, that recruit HDACs [56,[62][63][64][65][66][67] and histone methyltransefrases (HMTs) [68] on methylated targeted sequences. Acetylation of the α amino groups of evolutionary conserved lysine residues present on nucleosomal histone H3 and H4 is catalyzed by the histone acetyl transferases (HAT).…”

Arabidopsis histone deacetylase 6: a green link to RNA silencing

“…First, methylcytosine is targeted by methyl CpG-binding proteins (MBDs), which in turn can recruit transcriptional corepressors and/or chromatin remodeling proteins, histone deacetylases (HDACs) and histone methyltransferases (HMTs) (Bird and Wolffe, 1999;Wade et al, 1999;De Ruijter et al, 2003). MBDs are conserved across kingdoms and there is evidence that a subset of them is involved in interpreting DNA methylation also in plants (Zemach and Grafi, 2007).…”

Histone deacetylase modulators provided by Mother Nature

“…In addition to histone acetylation, other histone modifications such as methylation are involved in chromatin structure and act together with DNA methylation on TSG silencing ( Fig. 2; Florean et al 2011;Hassan et al 2007;Jones et al 1998;Wade et al 1999). Altogether, these mechanisms are implicated in apoptosis resistance, differentiation arrest, cell cycle perturbations leading to aberrant proliferation associated with tumorigenesis and tumor aggressiveness, including invasiveness and metastasis.…”