Mammals have limited regenerative potential. Regeneration is limited to certain cell types like our skin, gut intestinal cells, and blood. Tissue regeneration in mammals is restricted to organs such as the liver. Many cell types and tissues fail to regenerate including the inner ear. Damage to sensitive structures called hair cells in the inner ear is irreversible and results in hearing loss and deafness.
However, in nature, we find a number of organisms with the capacity to regenerate specialized cell types, tissues, organs, and even limbs. These animals can regenerate, so why can’t we?
“Why can some animals regenerate and others cannot?” is a fundamental question in regenerative biology. Our laboratory uses the zebrafish as a model system to answer this question because they are highly regenerative and can regrow amputated fin, lesioned brain, heart, spinal cord, and my favorite cell types called the hair cells. We use the adult zebrafish inner ear as a model system to study this profound question because the inner ear represents a fantastic model to study regeneration at a certain time and place. Our laboratory also uses the mouse as a model system to understand the barriers that actively block regeneration.
Project 1) Deciphering the logic functions of the Sox and Six genomic cis-regulatory code in response to sensory hair cell damage.
We have shown that the Sox and Six transcription factors (TFs) work in combination to regulate the expression of target genes by co-localization to the same enhancer regulatory regions, orchestrating cell-type, and cell-state specific gene regulation. Our research is focused on understanding the transcriptional basis of enhancer-mediated gene expression and downstream function of Six and Sox containing regulatory regions during hair cell regeneration.
Project 2) Investigating the biological significance of the newly identified gene regulatory networks using in vivo assays.
We have identified several cell-specific candidate enhancer regions with predicted roles in hair cell regeneration. Using zebrafish genetics and a knockout approach, we are systematically testing the functional relevance of the identified enhancers. The ultimate goal is to use our understanding of epigenomic regulation in zebrafish hair cell regeneration to predict and functionally validate in vivo a regeneration “enhanceome,” i.e. a list of enhancers that react to tissue injury in a stereotyped response.
Project 3) Identifying gene regulatory networks that differ between a regeneration competent and regeneration refractory inner ear.
We have identified a set of gene regulatory networks involved in the zebrafish hair cell regeneration program. The next step now is to test the universality of our findings and determine if the molecular responses we have identified in the regenerating zebrafish inner ear are conserved or species-specific.