MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome.

Abstract

Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6-18 months after birth. Here we report integrated analyses of genomic binding of MeCP2, gene-expression data, and patterns of DNA methylation. In addition to the expected high-affinity binding to methylated cytosine in the CG context (mCG), we find a distinct epigenetic pattern of substantial MeCP2 binding to methylated cytosine in the non-CG context (mCH, where H = A, C, or T) in the adult brain. Unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.

• Authors: Lin Chen, Kaifu Chen, Laura A Lavery, Steven Andrew Baker, Chad A Shaw, Wei Li, Huda Y Zoghbi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 17 Pg. 5509-14 (Apr 28 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25870282 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Mecp2 protein, mouse
• Methyl-CpG-Binding Protein 2
• DNA

Topics

• Animals
• Brain-Derived Neurotrophic Factor (biosynthesis, genetics)
• DNA (genetics, metabolism)
• DNA Methylation
• Disease Models, Animal
• Gene Expression Regulation
• Male
• Methyl-CpG-Binding Protein 2 (genetics, metabolism)
• Mice
• Mice, Transgenic
• Neurons (metabolism, pathology)
• Rett Syndrome (genetics, metabolism, pathology)
• Transcription, Genetic