Epigenetic Control of Genome Function in Brain Development and Disease
Key Words: Epigenetics, DNA Methylation, Chromatin, Neurodevelopment, Neural Circuit, Autism, Rett Syndrome
Description of Research
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, major depression 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 disorder 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 disorder
The term "CDKL5 disorder" refers to patients carrying genetic mutations in 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 in 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.
Awards and Honors
Harold M. Weintraub Graduate Student Award
Helen Hay Whitney Postdoctoral Fellowship
NIH Pathway to Independence Award (K99/R00)
IDDRC New Program Development Award
Pew Scholar in Biomedical Sciences
The BRAINS Award, NIH
Frank/Fay Seed Grant Award, Brain Research Foundation
Yolanda (Yue) Cui, Lab Manager
Darren Goffin, Postdoctoral Fellow
Janine Lamonica, Postdoctoral Fellow
Yingtao (Jerry) Zhao, Postdoctoral Fellow
Deborah Kwon, Postdoctoral Fellow
Brian Johnson, CAMB Graduate Student
Katie Wood, CAMB Graduate Student
Judy Wang, NGG Graduate Student
Maria Fasolino, NGG Graduate Student
Sarah Welsh, BMB Graduate Student
Jun Yeop Lee, Research Specialist
Hallene Guo, Research Specialist
Daniel Bu, Penn Undergrad
For research opportunities, please visit the Zhou Lab website.
Goffin D, Allen M*, Zhang L*, Amorim M*, Wang IT*, Reyes A, Mercado-Berton A, Ong C, Cohen S, Hu L, Blendy JA, Carlson G, Siegel S, Greenberg ME and Zhou Z: Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nature Neuroscience 15(2): 274-283, 2012.
Goffin D and Zhou Z: The neural circuit basis of Rett Syndrome. Frontiers in Biology 7(5): 428-435, 2012.
Wang IT, Allen M, Goffin D, Zhu X, Fairless AH, Brodkin ES, Siegel SJ, Marsh ED, Blendy JA and Zhou Z: Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proc Natl Acad Sci USA 109(52): 21516-21521, 2012.
Zhao YT*, Goffin D*, Johnson BS* and Zhou Z: Loss of MeCP2 function is associated with distinct gene expression changes in the striatum. Neurobiology of Disease 59C: 257-266, 2013.
Wang IT*, Reyes AR*, and Zhou Z: Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation. Neurobiology of Disease 58C: 3-12, 2013.
Bissonnette JM#, Schaevitz LD, Knopp SJ and Zhou Z : Respiratory phenotypes are distinctly affected in mice with common Rett syndrome mutations MeCP2 T158A and R168X. Neuroscience 267: 166-176, 2014.
Goffin D, Brodkin ES, Blendy JA, Siegel SJ and Zhou Z: Cellular origins of auditory event-related potential deficits in Rett syndrome. Nature Neuroscience 17(6): 804-806, 2014.
Kwon DY and Zhou Z: Trapping MBD5 to Understand 2q23.1 Microdeletion Syndrome. EMBO Molecular Medicine 6(8): 993-994, 2014.
back to top
Last updated: 11/26/2014
The Trustees of the University of Pennsylvania