Douglas J. Epstein, Ph.D.

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Professor of Genetics
Department: Genetics
Graduate Group Affiliations

Contact information
463 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104
Office: 215 573-4810
Fax: 215 573-5892
McGill University, 1986.
McGill University, 1989.
McGill University, 1993.
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Description of Research Expertise

Research Interests
Research in my lab focuses on two major themes: gene regulation during brain development and the genetic basis of inner ear morphogenesis. Both areas of investigation use mouse models to study mechanisms of human congenital disorders including brain malformations and hearing loss.

Key words: gene regulation, enhancers, Shh, brain development, hearing loss, cochlea, genetics, genomics, gene therapy

Description of Research
How is Sonic hedgehog expression regulated during brain development?
The Sonic hedgehog (Shh) gene is regulated by a well-characterized set of brain enhancers with essential roles in neurodevelopment. We use Shh enhancer knockout mouse models to:
•Study the mechanisms of enhancer redundancy and 3D folding dynamics of the locus in the developing brain
•Elucidate thalamic development and function
•Decipher neural circuits underlying abnormal motor and sensory information processing that occur in neurodevelopmental disorders

What is the genetic basis of congenital and adult-onset hearing loss?
Hearing loss is the most prevalent sensory deficit in humans. Approximately half of all cases of early onset hearing loss in developed countries have a genetic etiology, with single gene mutations in over 100 different loci identified so far. Despite this progress, the cause of inherited sensorineural hearing loss (SNHL) still remains uncertain in many cases. Remarkably, SNHL is even more common in adults, yet we know much less about the genetic architecture of hearing loss in the adult population. We interrogate the genetic basis of hearing loss:
•By leveraging whole exomes linked to electronic health records in the Penn Medicine Biobank
•As a multidisciplinary team with the Penn Center for Adult Onset Hearing Loss
•By generating mouse models of congenital and adult onset hearing loss, characterizing inner ear phenotypes, and designing novel treatment options

Rotation Projects
Several rotation projects related to the stated goals of the lab are currently available. Contact Dr. Epstein for more information.

Lab personnel:
Jailynn Harke (Graduate Student) co-mentored with Eric Joyce
Staci Rakowiecki (Research Specialist)
Tingfang Chen, Ph.D. (Postdoctoral Fellow)
Sixing Chen, M.Sc. (visiting scholar)
Paraskevi Sgourdou, Ph.D. (Postdoctoral Fellow)
Jeewon (Becca) Lee (Penn Vagelos Scholar)

Selected Publications

Chen T, Rohacek AM, Caporizzo M, Nankali A, Smits JJ, Oostrik J, Lanting CP, Kücük E, Gilissen C, van de Kamp JM, Pennings RJE, Rakowiecki SM, Kaestner KH, Ohlemiller KK, Oghalai JS, Kremer H, Prosser BL, Epstein DJ.: Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing. Developmental Cell 56: 1526-1540, 2021.

Muthu, V., Rohacek A.M., Yao, Y., Rakowiecki,S.M., Brown, A.S., Zhao, Y.T, Myers, J., Won, K.J, Ramdas, S., Brown, C.D., Peterson, K.A., and Epstein, D.J.: Genomic architecture of Shh dependent cochlear morphogenesis. Development 146: dev181339, 2019.

Corman, T.S., Bergendahl, S. and Epstein, D.J.: Distinct temporal requirements of Sonic hedgehog signaling in development of the tuberal hypothalamus. Development 145, 2018.

Rohacek AM, Bebee TW, Tilton RK, Radens CM, McDermott-Roe C, Peart N, Kaur M, Zaykaner M, Cieply B, Musunuru K, Barash Y, Germiller JA, Krantz ID, Carstens RP, Epstein DJ.: ESRP1 Mutations Cause Hearing Loss due to Defects in Alternative Splicing that Disrupt Cochlear Development. Developmental Cell 43: 318-331, 2017.

Kahn, B.M., Corman, T.S., Lovelace, K., Hong, M., Krauss, R.S. and Epstein, D.J. : Prenatal ethanol exposure in mice phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia. Disease Models and Mechanisms 10: 29-37, 2017.

Yao, Y., Minor, P.J., Zhao, Y-T., Jeong, Y., Pani, A.M. King, A.N., Symmons, O., Gan, L., Cardoso, W.V., Spitz, F., Lowe, C.J. and Epstein, D.J.: Cis-regulatory architecture of a brain-signaling center predates the origin of chordates. Nature Genetics 48: 575-580, 2016.

Brown, A.S., Rakowiecki, S.M., Li, J.Y. and Epstein, D.J. : The cochlear sensory epithelium derives from Wnt responsive cells in the dorsomedial otic cup. Developmental Biology 399: 177-187, 2015.

Trowe, M-O., Zhao, L., Weiss, A-C., Christoffels, V., Epstein, D.J.* and Kispert, A.* : Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for the formation of the neurohypophysis Development 140: 2299-2309, 2013 Notes: *corresponding authors.

Rakowiecki, S. and Epstein, D.J. : Divergent roles for Wnt/β-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Development 140: 1730-9, 2013.

Zhao, L., Zevallos, S., Rizzoti, K., Jeong, Y., Lovell-Badge, R. and Epstein, D.J.: Disruption of SoxB1 dependent Sonic hedgehog expression in the hypothalamus causes Septo-Optic Dysplasia. Developmental Cell 22: 585-596, 2012.

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Last updated: 06/08/2022
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