The Zhou Lab University of Pennsylvania School of Medicine  

Research Interest

A fundamental question in Genetics and Neuroscience is how the brain executes genetic programs while maintaining the ability to adapt to the environment. The underlying molecular mechanisms are not well understood, but epigenetic regulation, mediated by DNA methylation and chromatin organization, provides an intricate platform bridging genetics and the environment, and allows for the integration of intrinsic and environmental signals into the genome and subsequent translation of the genome into stable yet adaptive functions in the brain. Impaired epigenetic regulation has been implicated in many brain disorders, including monogenetic diseases such as CDKL5-related disorders and Rett Syndrome, and diseases with complex genetic traits such as epilepsy, depression, bipolar disorder, schizophrenia, and autism.

We are interested in understanding the epigenetic mechanisms that integrate environmental factors with genetic code to govern neural network formation and function in the brain, and how defects in this process may lead to intellectual disability. We use a combination of genomic and genetic approaches, together with cellular and behavioral assays in genetically modified mice, to investigate the dynamic changes of the epigenome, the functional interpretation of the epigenome, the molecular basis of adaptive behaviors, and the pathogenic mechanisms of CDKL5-related disorders and Rett Syndrome. It is our hope to ultimately translate our findings into therapeutic development.

1) Defining the epigenetic code underlying gene-environment interactions. The genetic underpinnings of mental health disorders are highly complex, involving multifaceted interactions between risk genes and the environment. It is known that environmental factors such as adverse early life events confer significantly greater susceptibility to psychiatric conditions later in life. But, the epigenetic mechanisms by which environmental factors interact with genetic programs in the nervous system remain poorly understood. We have developed novel genetically modified mice and aim to identify the epigenetic modifications, such as DNA methylation and histone modifications, induced by environmental factors in defined neural circuits and defined populations of neurons. We are interested in elucidating the signaling pathways that convert environmental signals to changes in the epigenome and how changes in the epigenome modulate animal behaviors.

2) Understanding the pathogenic mechanisms of CDKL5-related disorders. CDKL5-related disorders refer to patients carrying genetic defects on the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). Patients with CDKL5 dysfunction show early onset intractable seizures and severe neurodevelopmental impairment, and are frequently diagnosed with a number of disorders including Infantile Spasms, West Syndrome, Lennox-Gastaut, atypical Rett Syndrome, and Autism. To gain insight into the pathogenic mechanisms underlying CDKL5-related disorders, we have developed mouse models in which the Cdkl5 gene is ablated or modified. We found that loss of functional CDKL5 disrupts multiple signal transduction pathways, impairs event-related potentials, and leads to autistic-like phenotypes in mice. We plan to identify the molecular targets of CDKL5, dissect the signaling cascades responsible for autistic-like phenotypes, and investigate the neural mechanisms by which CDKL5 dysfunction leads to early onset seizures and cognitive deficits.

3) Elucidating the molecular basis of Rett Syndrome. Rett Syndrome (RTT) is an autism spectrum disorder characterized by developmental regression, motor dysfunction, and cognitive deficits. The majority of RTT cases are associated with mutations on an X-linked gene encoding MeCP2, a methyl-CpG binding protein involved in organizing chromatin and modulating gene expression. To understand the molecular pathogenesis of RTT, we have developed mouse models recapitulating RTT-associated mutations. We found that mice with RTT-associated MeCP2 T158A mutation show RTT-like phenotypes and deficits in neural circuitry. The T158A mutation decreases binding of MeCP2 to methylated DNA, reduces MeCP2 protein stability, and disrupts particular gene transcription and dendritic morphogenesis in a neuronal cell type-dependent manner. We aim to define the role of methyl-DNA binding of MeCP2 in protein stability, delineate the cellular origin of impaired neural circuitry, and elucidate the mechanisms by which MeCP2 modulates neuronal cell-type specific function.

4) Exploring the coding and decoding of the methylome in neurons. Cytosine methylation (5mC), mostly at CpG dinucleotides in mammals, is a central epigenetic mark essential for development. While we can now profile genome-wide DNA methylation at single-base resolution (sequencing methylome), how the methylome is established and maintained, and how the cell interprets the methylome to affect gene expression and chromatin structure remain poorly understood. Moreover, recent studies have challenged the stability of the methylome in postmitotic neurons and have coupled changes in DNA methylation at specific loci to adaptive behaviors. We are interested in understanding how DNA methylation is coded and decoded genome-wide but with locus-specificity in neurons. Given the high abundance of hydroxymethylcytosine (5hmC) in the brain, we set up to address the functional significance of 5mC and 5hmC in neural development, the role of the methylome in the establishment of neuronal identity, and the molecular mechanisms by which the methylome modulates genome function in the brain.