Heart disease is the leading cause of death in the world today. A central feature of heart disease is the permanent loss of heart muscle, which regenerates very poorly in humans. Unlike humans, zebrafish can replenish up to 60% of lost heart muscle or cardiomyocytes (CM) without adverse effects or scarring. Only some of the factors involved in this regeneration have been identified; others remain to be discovered. One major challenge has been to reveal master regulators that define regenerative capacity.
The long-term goal of my laboratory is to identify the gene regulatory network that governs regeneration. Transcriptional control is likely a key feature of regeneration competency as thousands of genes change in expression. As primary determinants of gene regulation, transcription factors not normally active in uninjured CMs are likely required for triggering regeneration. Yet, the identity of these factors remains elusive. Similarly, changes in chromatin packaging integral during development may likewise underpin competency for regeneration. Nucleosome reorganization may be a critical feature of normally dormant cis- regulatory elements and promoters. My research program aims to identify novel transcription factors and chromatin regulation governing zebrafish heart regeneration.
Project 1: Defining a transcription factor network for regeneration
Previously, I generated a compendium of cis-regulatory elements emerging in regenerating CMs. I validated several of these enhancers by making transgenic fish with reporter alleles that drive gene expression in proliferating CM. From this data set, we were also able to extract transcription factor motifs enriched in activated regions of the genome, leading to candidates of a gene regulatory network. The goal of this first project is to identify the minimal DNA sequence that directs expression during regeneration and to determine the transcription factors integral to its regulation by making transgenic and mutant fish.
Project 2: Identifying changes in chromatin structure that underlie regeneration
From high-throughput mapping of histone architecture, we observed genome-wide changes in chromatin accessibility that accompany regeneration. The goal of this second project is to uncover the nature of these changes in higher detail and to identify the chromatin regulatory factors that are mediating them. This project will include both chromatin profiling assays and construction of transgenic fish.
Project 3: Induction of protein translation promotes regeneration
Gene expression requires not just production of the mRNA transcript but also translation of the mRNA into protein by the ribosome. Using ribosome profiling on regenerating zebrafish hearts, we have found that hundreds of mRNA are changing in their association with the ribosome. The goal of this third project is to identify signatures within mRNA that regulate expression changes during regeneration.
Education and Training
BS - University of California, Los Angeles
PhD - Harvard Medical School
Postdoc - Duke University
Office: 105 Rightmire
Lab: 119 Rightmire