Mutations in the Methyl-CpG binding protein 2 gene (MeCP2) cause Rett syndrome, an autism spectrum disorder. RTT is hypothesized to result from deficient neuronal maturation and plasticity, possibly through abnormal experience-dependent synapse development and maintenance. MeCP2 has been implicated in chromatin and transcription regulation through binding to methyl-cytosines, which includes 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC). While 5mC is generally viewed as a silencing mark, 5hmC might represent methylation dynamics and play complex roles in gene regulation. However, the genomic distributions of 5mC and 5hmC in brain cells are poorly characterized, and it is unclear how MeCP2 might interpret 5mC and 5hmC patterns, thereby influencing transcription. It remains controversial whether MeCP2 is primarily a transcriptional repressor that modulates gene-specific targets or act globally in chromatin regulation. Identifying the transcriptional impact is a critical step toward understanding the mechanism of MeCP2 function. Characterizing altered transcription in relevant brain regions, neuron types, developmental and physiological context in mouse models is necessary for unraveling the pathogenic mechanism of RTT. A key challenge in studying the role of MeCP2 in gene regulation in the brain is cellular heterogeneity. For example, it has been difficult to achieve high-resolution mapping of methylome in defined neuron types. Further, nerve cells modify their epigenomes and transcriptomes during development and in response to neuronal input. Thus an additional challenge is to examine functionally relevant cells in an appropriate developmental and plasticity context. We have developed methods and experimental systems for cell-based genomic analysis and for studying MeCP2 in a well established paradigm of cortical plasticity. Our General Hypothesis is that by tracking genome wide 5mC and 5hmC distributions and dynamics, MeCP2 regulates chromatin structures and gene transcription in a cell type- and cell state-dependent manner during experience-dependent neuronal maturation. We will apply cell-based analysis of DNA methylome (including 5mC and 5hmC) and transcriptome to examine the relationship among these profiles in cortical glutamatergic and GABAergic neurons during postnatal maturation. We will then examine the impact of MeCP2 mutations on methylomes and transcriptome in these neurons. We will further examine whether MeCP2 functions as an activity-regulated brake of experience-driven maturation of parvalbumin-positive GABA interneurons, which time the onset and progression of the critical period plasticity in primary visual cortex. Combining cell specificity, base resolution analysis of methylomes and their impact on transcriptomes in a well-defined context of neural development, these studies will provide insight into the regulatory relationships among cytosine methylation, MeCP2 function and gene expression, a fundamental issue in epigenetic regulation of the brain.
We aim to reveal the developmental trajectory and genetic architecture of MeCP2 mutation and suggest strategies for intervention for RTT.
|Chen, Fei Xavier; Xie, Peng; Collings, Clayton K et al. (2017) PAF1 regulation of promoter-proximal pause release via enhancer activation. Science 357:1294-1298|
|Jia, Chen; Xie, Peng; Chen, Min et al. (2017) Stochastic fluctuations can reveal the feedback signs of gene regulatory networks at the single-molecule level. Sci Rep 7:16037|
|Paul, Anirban; Crow, Megan; Raudales, Ricardo et al. (2017) Transcriptional Architecture of Synaptic Communication Delineates GABAergic Neuron Identity. Cell 171:522-539.e20|
|Vogt, Daniel; Cho, Kathleen K A; Shelton, Samantha M et al. (2017) Mouse Cntnap2 and Human CNTNAP2 ASD Alleles Cell Autonomously Regulate PV+ Cortical Interneurons. Cereb Cortex :1-12|
|Krishnan, Keerthi; Lau, Billy Y B; Ewall, Gabrielle et al. (2017) MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice. Nat Commun 8:14077|
|Chen, Yong; Wang, Yunfei; Xuan, Zhenyu et al. (2016) De novo deciphering three-dimensional chromatin interaction and topological domains by wavelet transformation of epigenetic profiles. Nucleic Acids Res 44:e106|
|Crow, Megan; Paul, Anirban; Ballouz, Sara et al. (2016) Exploiting single-cell expression to characterize co-expression replicability. Genome Biol 17:101|
|He, Miao; Tucciarone, Jason; Lee, SooHyun et al. (2016) Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex. Neuron 91:1228-1243|
|Wang, Tao; Xiao, Guanghua; Chu, Yongjun et al. (2015) Design and bioinformatics analysis of genome-wide CLIP experiments. Nucleic Acids Res 43:5263-74|
|Krishnan, Keerthi; Wang, Bor-Shuen; Lu, Jiangteng et al. (2015) MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc Natl Acad Sci U S A 112:E4782-91|
Showing the most recent 10 out of 12 publications