Our Research

How do enhancers regulate Sonic hedgehog (Shh)
expression during brain development?

We focus on Shh enhancers that control unique and overlapping patterns of expression in the developing forebrain

  • We are spatially reconstructing the Sonic hedgehog (Shh) locus in the developing brain. Our aim is to reveal whether sites of Shh transcription in the embryo, which are coordinated by multiple partially redundant enhancers, are dependent on a simple looping mechanism, or if more complex regulatory interactions are at play.

    We use:
    Oligopaints and super resolution microscopy to address how cis and trans-acting determinants of Shh genomic architecture influence Shh expression in the developing brain

  • Despite advances in our understanding of early roles for Shh in forebrain development, we still lack an accurate account of the number and molecular profiles of distinct neural progenitor subtypes, intermediate progenitors and mature neurons that make-up the thalamus, a key sensory and motor information processing center. We are defining the molecular signatures, lineage trajectories and Sonic hedgehog (Shh) dependencies of thalamic progenitor subtypes through:

    • single-cell RNA-seq (scRNA-seq), a potent method for unbiased discovery of cell types and states, to determine the full complement of thalamic progenitors and their transcriptional trajectories as they differentiate and aggregate into discrete thalamic nuclei.

  • We are deconstructing the spatiotemporal role of Sonic hedgehog (Shh) signaling in thalamic development and function to reveal new mechanisms of neurological disease that manifest from perturbations in thalamic development. We interrogate Shh brain enhancer knockout mice to determine the full effect that disruption of Shh expression has on thalamic formation through:

    multiplexed single molecule in-situ methods for quantitative analysis of gene expression

    examination of defects in thalamic circuit assembly, as well as in motor and sensory behaviors

What is the genetic basis of adult-onset hearing loss?

The identification of gene mutations associated with hearing loss in humans and animal models has contributed greatly to our understanding of cell type specific functions in the inner ear. Research in the Epstein lab is strongly motivated by the premise that a detailed elaboration of the molecular and cellular mechanisms of cochlear development and function will not only provide better insight into the workings of this complex sensory organ, but may also profoundly change the way inner ear disorders, including hearing loss, are treated in the future.

  • 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. Mutations in the majority of these genes result in nonsyndromic sensorineural hearing loss (SNHL), where abnormal inner ear function is the only diagnostic feature. In comparison to children, the genetic causes of hearing loss in adults remain poorly understood. Approximately, 80% of hearing loss cases are diagnosed after the second decade of life and yet, adults are rarely tested for genetic mutations as a possible cause of their condition. To address this gap in knowledge we created the Center for Adult Onset Hearing Loss (CAOHL), a strategic partnership between the Departments of Otolaryngology and Genetics, as well as the Penn Medicine Biobank. The primary goal of the Center is to determine the genetic architecture of hearing loss in adult populations. A multidisciplinary team works in close collaboration to identify patients likely to harbor mutations associated with progressive adult-onset hearing loss, determine their genetic risk, screen for those likely to be amenable to intervention, develop mouse models, therapeutics, and ultimately implement those therapies in the clinic. The principle investigators have relevant and complementary expertise in the clinical and basic scientific fields necessary for this work. The approach is novel not only for the team involved, but also for the University, and the field at large. Specifically, investigating the genetic underpinnings of hearing loss in adults is highly innovative, as the majority of work in this field has focused on congenital hearing loss which represents a small minority of clinically relevant cases.