Methyl-CpG-binding protein 2 (MeCP2) was first purified over twenty years ago and identified as a transcriptional repressor that binds to methylated CpG dinucleotides. Eleven years ago our lab discovered that mutations in the X-linked MECP2 gene cause Rett Syndrome (RTT, MIM312750). We now know that MECP2 mutations (as well as duplications or triplications of the wild-type gene) cause a variety of neuropsychiatric disorders, ranging from neonatal encephalopathy to autism, various kinds of cognitive and motor impairments, and early-onset psychosis in males and females. It also appears that MeCP2 is not a straightforward transcriptional repressor. Through work supported by the last renewal of this grant, we made the surprising discovery that MECP2 overexpression increases the expression levels of 80% of the hypothalamic genes it appears to regulate, whereas loss of MeCP2 results in decreased expression of the same genes. More puzzling still, chromatin immunoprecipitation (ChIP)-chip and ChIP-seq data as well as locus-specific ChIP data show that MeCP2 binds widely throughout the genome but that it is especially concentrated at specific promoters. How MeCP2 binding to promoter or non-promoter DNA increases neuronal gene expression is unclear. We hypothesize that MeCP2 modulates chromatin architecture but that it also has unique functions at select neuronal promoters. In our first aim, therefore, we will map the genome-wide occupancy of MeCP2 in the brain and compare the results with our existing expression data in MeCP2 mouse models to determine if there is a relationship between MeCP2 promoter occupancy and changes in gene expression. In our second aim, we will test the hypothesis that MeCP2 serves as an alternative linker histone, and determine whether there is an essential balance between MeCP2 and H1 levels in brain tissue, as well as elucidate the functional relationship between these two factors. In the third aim, we will examine MeCP2 interactions with the chromatin remodeling protein Ezh1 (an in vivo partner of MeCP2 we recently identified, whose spatiotemporal expression pattern parallels that of MeCP2);in both aims 2 and 3 we will test how these interactions might mediate MeCP2 phenotypes through the generation of new mouse models. Finally, our fourth aim extends our work suggesting that altering gene expression might mitigate RTT and MeCP2 duplication phenotypes. We will test therapies targeting chromatin status (HDAC and HAT inhibitors) in mouse models of RTT and MECP2 duplication syndrome. These four aims will settle several fundamental questions about MeCP2's roles in transcription, will yield important insights into chromatin alterations in neurons that cannot be approached without in vivo studies, and could yield promising candidate therapies.

Public Health Relevance

Mutations in MECP2 cause Rett syndrome as well as a host of other neuropsychiatric disorders. Our recent progress has led to possible therapeutic approaches we will test in our well-characterized mouse models, while we also seek to answer fundamental questions about MeCP2's influence on neuronal gene transcription.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Developmental Brain Disorders Study Section (DBD)
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Mamounas, Laura
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Baylor College of Medicine
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Zoghbi, Huda Y; Beaudet, Arthur L (2016) Epigenetics and Human Disease. Cold Spring Harb Perspect Biol 8:a019497
Meng, Xiangling; Wang, Wei; Lu, Hui et al. (2016) Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. Elife 5:
Lu, Hui; Ash, Ryan T; He, Lingjie et al. (2016) Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model. Neuron 91:739-47
Ure, Kerstin; Lu, Hui; Wang, Wei et al. (2016) Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife 5:
Lombardi, Laura Marie; Baker, Steven Andrew; Zoghbi, Huda Yahya (2015) MECP2 disorders: from the clinic to mice and back. J Clin Invest 125:2914-23
Sztainberg, Yehezkel; Chen, Hong-mei; Swann, John W et al. (2015) Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528:123-6
Pohodich, Amy E; Zoghbi, Huda Y (2015) Rett syndrome: disruption of epigenetic control of postnatal neurological functions. Hum Mol Genet 24:R10-6
Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei et al. (2015) Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes. Neuron 88:651-8
Baker, Steven Andrew; Lombardi, Laura Marie; Zoghbi, Huda Yahya (2015) Karyopherin α 3 and karyopherin α 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. J Biol Chem 290:22485-93
Hao, Shuang; Tang, Bin; Wu, Zhenyu et al. (2015) Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature 526:430-4

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