Biomedical Graduate Studies

Description of Research Expertise

Research Interest
Genetics and Epigenetic Control of Genome Function in Brain Development and Disease

Key Words: Neurogenetics, Neuroepigenetics, DNA Methylation, Histone Modification, Genomic Editing, CRISPR, Autism, CDKL5 Deficiency Disorder, Major Depression, 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 histone modification, provides an intricate platform bridging genetics and the environment. This regulation enables the integration of internal and external signals into the genome, translating genetic information into stable yet adaptive neuronal functions in the brain. Impairments in epigenetic regulation have been linked to multiple neurodevelopmental and neuropsychiatric disorders.

The Zhou laboratory is devoted to unraveling these epigenetic mechanisms, particularly how disruptions in epigenetic pathways contribute to the pathogenesis of neurodevelopmental and neuropsychiatric disorders. These include Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD), which have clear genetic origins; autism spectrum disorder (ASD), characterized by complex genetics; and major depressive disorder (MDD), influenced by environmental factors. We employ cutting-edge genomic technologies along with cellular and physiological assays in genetically modified mouse and human induced pluripotent stem cell (hiPSC) models to explore the underlying pathophysiology. Our goal is to translate these discoveries into therapeutic interventions that enhance the quality of life for individuals affected by RTT, CDD, ASD or MDD.

1) Understanding the molecular basis of stress vulnerability

Stressful life events can increase the risk of developing neuropsychiatric conditions such as anxiety and depressive disorders. However, not everyone exposed to stress will develop these conditions. By investigating the molecular basis of stress vulnerability, we aim to better understand the etiology of major depressive disorder (MDD) and develop effective strategies for its prevention, diagnosis, and treatment. Given that the effects of stress on the brain and behavior are evolutionarily conserved across species, we have generated genetically modified mouse models to study stress-induced epigenomic changes. These models enable us to explore how stress alters gene expression across the genome. Additionally, we have designed experimental paradigms to investigate the functional relationships between these epigenetic changes and the emergence of maladaptive behaviors.

2) Pathogenic insights into X-linked Rett syndrome and CDKL5 deficiency disorder

X-linked refers to the characteristics or traits that are influenced by genes on the X chromosome. In females, one of the two X chromosomes undergoes random inactivation, resulting in both males and females having only one active X chromosome per cell. This process, known as X chromosome inactivation (XCI), leads to mosaic expression of X-linked genes at the cellular level, posing a significant challenge in studying X-linked disorders, particularly those that are dominant in heterozygous females, such as Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD). To address this challenge, we have developed hiPSC and mouse models that overcome X-linked cellular mosaicism in females. These models equip us to study RTT and CDD pathophysiology at both the individual cell and synaptic levels.

3) Epigenetic regulation of synaptic gene expression in the brain

Human genetic studies have repeatedly identified mutations in various chromatin-related factors—such as the DNA methylation 'writer' protein DNMT3a, the 'reader' protein MeCP2, specific histone methyltransferases (KMTs), histone demethylases (KDMs), and chromatin remodelers like CHDs—as being frequently associated with autism spectrum disorders (ASD). Given the critical roles these factors play in neural development, synaptic plasticity, and the brain's ability to adapt to environmental changes, we have focused on investigating how DNA methylation interacts with different histone modifications and how defects in these epigenetic mechanisms contribute to the development of ASD. By employing genome-wide and cell type-specific profiling techniques, along with CRISPR-mediated epigenomic editing, we aim to dissect the regulatory relationship between DNA methylation and histone modifications and how they collaboratively regulate the expression of synaptic genes.

Experimental Techniques and Themes:

“-Omics” studies using bulk and single-cell next-generation sequencing technologies; Epigenetic remodeling using adapted CRISPR-editing systems; Mouse phenotyping upon genetic or pharmacological interventions; Examination of neuronal connectivity in vivo with confocal microscopy; Analysis of neural circuit function with electrophysiology; Biochemical characterization of signal transduction pathways, and more.

Please feel free to reach out to Joe to discuss specific rotation projects

Current Lab Members

Monica Zielinski, Research Specialist/Lab Manager
Zijie (Jack) Xia, Postdoctoral Fellow
Joanna Medina, Postdoctoral Fellow
Matthew Edwards, Postdoctoral Fellow
Mingjia Li, PhD Student in CAMB
Yanjie Zhang, Research Specialist

Undergraduate Research Assistants
Maria Villela, Hannah Kim, Shambhabi Gautam, Averie Wu

Previous Trainees

Darren Goffin (Postdoc 2009-2014), IRSF sponsored postdoctoral Fellow, now Assistant Professor and Lecturer at the University of York; Judy Wang (PhD Student in NGG 2010-2014), Behavioral and Cognitive Neuroscience TG32 Trainee, Winner of Tom Kadesch Prize in Genetic Research, now Director of Business Development at Linus Health; Brian Johnson (PhD Student in CAMB 2010-2016), Trainee of CMB TG32, UNCF/Merck Graduate Science Research Awardee, now Postdoc Fellow at Stanford University; Le Zhang (Postdoc 2010-2011), now Assistant Professor at Yale University; Kathleen Wood (PhD Student in CAMB 2011-2016), Trainee of Genetics TG32, now Clinical Genomic Scientist at Children's Hospital of Philadelphia; Erina Hara (Postdoc 2011-2012), now Scientific Research Project Manager at Columbia University Irving Medical Center; Janine Lamonica (Postdoc 2012-2018), IRSF sponsored postdoctoral Fellow, now Senior Research Investigator and Project Lead in the Gene Therapy Program at University of Pennsylvania; Yingtao (Jerry) Zhao (Postdoc 2012-2019), now Assistant professor at the New York Institute of Technology; Maria Fasolino (PhD Student NGG 2013-2017), now Scientific Director of the Autism Spectrum Program of Excellence (ASPE) at the University of Pennsylvania; Deborah Kwon (Postdoc 2013-2020), Recipient of Neurodevelopmental Disabilities TG32, now Scientist at Biogen; Sheng Tang (MD/PhD Student in NGG 2015-2018), Recipient of NIH/NRSA F30 Fellowship, now Resident Fellow at the Medical Center of Northwestern University; Barbara Terzic (PhD Student in NGG 2015-2020), Recipient of NIH/NRSA F31 Fellowship, Saul Winegrad Awardee for Outstanding Dissertation, now Research Scientist at Spark Therapeutics; Bing Xu (Postdoc 2019-2021), now Associate Investigator at the First Affiliated Hospital of Shandong First Medical University; Andrew Edmondson (Postdoc 2018-2021), NIH K08 Awardee, now Assistant Professor at Children's Hospital of Philadelphia and University of Pennsylvania; Xie Philip song (Postdoc 2021-2023), now Hepatobiliary Surgeon at Shandong University Hospital; Daniel Connolly (MD/PhD Student in NGG 2020-2023), Recipient of NIH/NRSA F30 Fellowship, now MSTP student at the Hospital of the University of Pennsylvania. Dayne Martinez (MD/PhD Student in NGG 2021-2024), now MSTP student at the Hospital of the University of Pennsylvania.

Research Specialists/Post-Baccalaureate Students
Maria Amorim (2009-2010), Graduate Student at Hospital A.C. Camargo; Megan Allen (2009-2011), Graduate Student at Georgetown University; Nicha Ubol (2011-2012), Nursing Student at Rutgers University; Arith Reyes (2012-2013), Medical Student at the Washington University In St. Louis; Hallene Guo (2014-2015), Medical Student at the University of Maryland; Jun Yeop Lee (2013-2015); Medical Student at Mount Sinai Icahn School of Medicine; Jie Zhou (2018-2019), Graduate Student at the University of Connecticut; George Gardner (2018-2019), Medical Subscriber at the Hospital of the University of Pennsylvania; Joshua Ross (2020-2021), Consultant at Blockfolio; Erin Nugent (2019-2021), Scientist at Carisma Therapeutics; Emily Guo (2020-2022), Medical Student at Yale School of Medicine; Yaohao Zhang (2022-2024), Graduate Student at the University of Pennsylvania; Remy Stuckey (2022-2024), ER Assistant at the Huntsville Hospital; Zachary Spritzer (2022-2024), Graduate Student at Yale School of Medicine.

Undergraduate Students
Arith Reyes (2009-2012); Suzie Hong (2010-2013); Naomi Hachen (2010); Bryan Cam (2011-2012); Serena Zhou (2011-2012); Diana Nwokoye (2013); Olivia Rabe (2013); Hallene Guo (2013-2014); Daniel Bu (2013-2016); Katarina Pance (2016-2017); Zhou Zhou (2017); Hansoo Chang (2017); Katherine Sizov (2016-2018); Nicolas Sarmiento (2016-2019); Christine Liu (2017-2020); Dasha Zaitseva (2018-2021); Isabel Zhang (2019-2021); Dennis Fleysh (2021); Melody Yu (2021); Elana Grajales (2021); Amy Fang (2020-2021); Cadmus Cai (2021-2022); Emily Guo (2019-2022); Sharleen Banatte (2023); Yanjie Zhang (2021-2024); Sumiya Olson (2020-2024); Kaitlyn Green (2024); Endy Huynh (2024).