Figure 1

Epigenetic alterations in CM. Epigenetic regulation of gene expression involves the interplay of DNA methylation, histone modifications and miRNAs. A. Transcriptionally inactive genes (crossed red arrow) are characterized by the presence of methylated cytosines within CpG dinucleotides (grey circles), which is carried out and sustained by DNA methyltransferases (DNMT). Transcriptional repression may directly derive from methylated recognition sequence preventing the binding of transcription factors, or may be a consequence of the binding of methyl-CpG-binding proteins (MBP), which recruit chromatin remodelling co-repressor complexes. Transcriptionally active genes (green arrow) contain demethylated CpG dinucleotides (green circles), which prevent the binding of MBP and co-repressor complexes, and are occupied by complexes including transcription factors and co-activators. B. Histones are subjected to a variety of post-translational modifications on their amino terminus (N), including methylation and acetylation, which determine chromatin structure, resulting in the modulation of accessibility of DNA for the transcriptional machinery. The acetylation status of histones is controlled by the balanced action of histone acetyltransferases and histone deacetylases, and acetylated histones have been associated with actively expressed genes. Histone methylation may have both repressive (H3K9, H3K27) or promoting (H3K4) effects on transcription, depending on which residue is modified. C. MiRNAs are small non-coding RNAs that regulate the expression of complementary mRNAs. Once incorporated into the RNA-induced silencing complex, miRNAs recognize their target mRNA through a perfect or nearly perfect sequence complementarity, and direct their endonucleolytic cleavage or inhibit their translation. DICER, RNase III family endoribonuclease, ORF, open reading frame.