Further Development 3.5: Mechanisms of how DNA Methylation Blocks Transcription

DNA methylation appears to act in two ways to repress gene expression. First, it can block the binding of transcription factors to enhancers. Several transcription factors can bind to a particular sequence of unmethylated DNA, but they cannot bind to that DNA if one of its cytosines is methylated. Second, a methylated cytosine can recruit the binding of proteins that facilitate the methylation or deacetylation of histones, thereby stabilizing the nucleosomes. For instance, methylated cytosines in DNA can bind particular proteins such as MeCP2.¹ Once connected to a methylated cytosine, MeCP2 binds to histone deacetylases and histone methyltransferases, which, respectively, remove acetyl groups (Figure 1A) and add methyl groups (Figure 1B) on the histones. As a result, the nucleosomes form tight complexes with the DNA and do not allow other transcription factors and RNA polymerases to find the genes. Other proteins, such as HP1 and histone H1, will bind and aggregate methylated histones (Fuks 2005; Rupp and Becker 2005). In this way, repressed chromatin becomes associated with regions where there are methylated cytosines.

¹ Loss of MeCP2 in humans is the leading cause of an X-linked syndrome resulting in encephalopathy (brain disorder) and early death in males, and Rett syndrome (a neurological disorder that displays symptoms within the autism spectrum disorder) in females. MeCP2 may act through a signaling pathway (mTOR) to affect synaptic plasticity (Pohodich and Zoghbi 2015; Tsujimura et al. 2015).

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