We focus on uncovering epigenome-driven gene programs that promote progenitor cell differentiation into neuroendocrine cells. As a model, we study the mouse olfactory placode, the primary birthplace of gonadotropin-releasing hormone (GnRH) neurons, which control fertility and reproduction. Abnormal GnRH neuron development and function are hallmarks of a disorder called Kallmann syndrome, where patients do not undergo puberty and are infertile.
Our long-term goal is to develop therapeutics that prevent the onset of these types of neuroendocrinological diseases.
Research topic 1: Determine the epigenetic control of FGF8 expression during embryonic neuroendocrine development
Here, we explore how the epigenome controls DNA and histone modifications to modulate fibroblast growth factor (FGF) 8 transcription, required for progenitor cell development into GnRH neurons. Investigating this neuroendocrine system gives us a physiologically relevant model to identify and understand how epigenetic molecules control FGF8 transcription in the mouse fetus. We use various molecular and cellular techniques, such as chromatin-immunoprecipitation, MeDIP, DNA sequencing, cell tissue cultures, and embryonic mouse tissue explants. Our data confirmed the hypothesis that embryonic FGF8 transcription depends on the interaction of epigenetic enzymes with DNA and histones. The main outcome is a better appreciation of the epigenetic molecular mechanisms needed to control embryonic brain gene programs that facilitate normal and healthy brain function.
Research topic 2: Determine the molecular control of FGF8-dependent neural cell maturation and function
Our second research topic is to understand how FGF8 affects neural cell maturation. FGF8 is required for normal maturation of neuroendocrine cells that express vasopressin, oxytocin, and kisspeptin neurons. We also discovered that FGF8 disruption delays perinatal astrocyte maturation, which coincided with corpus callosum agenesis. Together these data indicate that FGF8 function is important for the continual maturation of neural cells, and led us to ask whether delayed neural cell maturation is detrimental for their adult cellular functions. Therefore, we study the responsiveness of adult neural cells to external stressors, such as ethanol or cuprizone (a demyelinating agent), which resulted in the discovery that adult transgenic mice with reduced FGF8 expression are hyper-responsive to stress and more anxious compared to wildtype mice. We also found that astrocyte reactivity to cuprizone is compromised in the same transgenic mouse. Therefore, we concluded that FGF8 continues to be of importance in the adult brain.
PhD students interested in the epigenetic control of gene transcription, neuroendocrine cell development and function, are welcome and can enter the lab through the Department of Biological Sciences (https://www.kent.edu/biology/graduate-programs) or the School of Biomedical Sciences (https://www.kent.edu/biomedical/graduate-programs-faculty).
Kent State undergraduates who are interested in Developmental Neuroscience, and want to learn research techniques, such as cell culture, embryonic brain tissue explants, DNA/RNA isolation, quantitative PCR, protein analysis and immunocytochemistry should contact Dr. Chung (firstname.lastname@example.org) to setup an appointment. Please include in the email a short description of your interests.
Handa RJ, Chung WCJ (2019) Gender and stress. In: Handbook of Stress: Physiology, Biochemistry and Pathology, Vol 3. (Fink G Ed). San Diego: Academic Press: 116 - 176.
Kim CK, Torcaso A, Asimes AD, Chung WCJ, Pak TR (2018) Structural and functional characteristics of estrogen receptor beta (ERβ) splice variants: implications for the aging brain. Journal of Neuroendocrinology.
Stewart CE, Corella KM, Samberg BD, Jones PT, Linscott ML, Chung WCJ (2016) Perinatal midline astrocyte development is impaired in fibroblast growth factor 8 hypomorphic mice. Brain Research. 1646: 287.
Linscott ML, Chung WCJ (2016) Fibroblast growth factor 8 expression in GT1-7 GnRH-secreting neurons is androgen-independent, but can be upregulated by the inhibition of DNA methyltransferases. Frontiers Cell and Developmental Biology. 4: 34.
Rodriguez KM, Stevenson EL, Stewart CE, Linscott ML, Chung WCJ (2015). Fibroblast growth factor 8 regulates postnatal development of paraventricular nucleus neuroendocrince cells. Behavioral Brain Functions. 11: 34.
Stevenson EL, Corella KM, Chung WCJ (2013) Ontogenesis of gonadotropin-releasing hormone neurons: a model for hypothalamic neuroendocrine cell development. Front Endocrinol. 4: 89.
Miraoui H, Dwyer AA, Sykiotis GP, Plummer L, Chung WCJ, et al (2013) Genetic screening of the FGF8 synexpression group identifies rare sequence variants in FGF17, IL17RD, DUSP6, SPRY4 and FLRT3 in patients with Congenital Hypogonadotropic Hypogonadism. American Journal of Human Genetics. 92: 725.
Rao YS, Mott NM, Wang Y, Chung WCJ, Pak TR (2013) A subset of miRNAs are differentially regulated by estrogen in the aging brain. Endocrinology. 154: 2795.
Chung WCJ, Auger AP (2013). Gender differences neurodevelopment and epigenetics. Pflugers Archiv. 465: 573.
Tsai TS, Brooks LR, Rochester JR, Kavanaugh SI, Chung WCJ (2011) Fibroblast growth factor signaling in the developing neuroendocrine hypothalamus. Frontiers of Neuroendocrinology.32: 95.
Chung WCJ, Matthews TA, Tata BK, Tsai PS (2010) Compound deficiencies in multiple FGF signaling components differentially impact the murine GnRH system.J Neuroendocrinology. 22: 944.
Chung WCJ, Moyle SS, Tsai PS (2008) Fibroblast growth factor 8 signaling through FGF receptor 1 is required for gonadotropin-releasing hormone neuronal development in mice. Endocrinology. 149: 4997.
Falardeau J, Chung WCJ, Beekeen A, Plummer L, Sidis Y, Raivio T, Dwyer A, Na S, Hall J, Huot C, Alois N, Quinton R, Cole LW, Hughes V, Mohammadi M, Tsai PS, Pitteloud N (2008). Decreased FGF8 signaling causes GnRH deficiency in human and mice. J Clin Invest. 118: 2822.
Chung WCJ, Pak TR, Suzuki S, Pouliot WA, Andersen ME, Handa RJ (2007). Detection and localization of an estrogen receptor beta splice variant protein (ERbeta2) in the adult female rat forebrain and midbrain regions. J Comp Neurol.20: 249.
Pak TR, Chung WCJ, Hinds LR, Handa RJ (2007) Estrogen receptor-beta mediates DHT-induced stimulation of the arginine vasopressin promoter in neuronal cells. Endocrinology. 148:3371.
Pak TR, Chung WCJ, Roberts JL, Handa RJ (2006) Ligand-independent effects of estrogen receptor beta on mouse gonadotropin releasing hormone (GnRH) promoter activity. Endocrinology 147: 1924.
Chung WCJ, De Vries GJ, Swaab DF (2002) Sexual differentiation in the bed nucleus of the stria terminalis of the human extends into adulthood. J Neurosci 22: 1027.
Chung WCJ, Swaab DF, De Vries GJ (2000) Apoptosis during postnatal sexual differentiation of the bed nucleus of the stria terminalis in the rat brain. J Neurobiology 43: 234.