title: 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: Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030.
authors: Lin
authors: L
authors: Chen
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, and.
authors: Kaifu
authors: K
authors: Chen
authors: Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030.
authors: Laura A
authors: LA
authors: Lavery
authors: Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030.
authors: Steven Andrew
authors: SA
authors: Baker
authors: Department of Molecular and Human Genetics.
authors: Chad A
authors: CA
authors: Shaw
authors: Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, and WL1@bcm.edu hzoghbi@bcm.edu.
authors: Wei
authors: W
authors: Li
authors: Department of Molecular and Human Genetics, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030 Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030; and WL1@bcm.edu hzoghbi@bcm.edu.
authors: Huda Y
authors: HY
authors: Zoghbi
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D004247:DNA
keywords: MeCP2; Non-CpG methylation; Rett syndrome; mCH; transcriptional regulation