Further Development 3.5: Mechanisms of how DNA Methylation Blocks Transcription

Differential Gene Expression: Mechanisms of Cell Differentiation

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).

Figure 1 Modifying nucleosomes through methylated DNA. MeCP2 recognizes the methylated cytosines of DNA. It binds to the DNA and is thereby able to recruit (A) histone deacetylases (which take acetyl groups off the histones) or (B) histone methyltransferases (which add methyl groups to the histones). Both modifications promote the stability of the nucleosome and the tight packing of DNA, thereby repressing gene expression in these regions of DNA methylation. (After F. Fuks. 2005. Curr Opin Genet Dev 15: 490–495.)

All the material on this website is protected by copyright. It may not be reproduced in any form without permission from the copyright holder.

Printed from , all rights reserved. © Oxford University Press, 2022