Examining the Role of the chromatin remodeler CHD5 in Tumor Suppression and Neural Differentiation in Zebrafish

Abstract

Gene expression and neurogenesis in vertebrates involves a wide variety of cellular machinery to coordinate the transcriptional changes that direct cellular differentiation. Critical aspects of this epigenetic machinery are chromatin remodeling factors. One such factor is CHD5, a vertebrate‐specific member of a family of ATP‐dependent chromatin remodeling proteins. CHD5 is expressed primarily in neural tissue where it is thought to contribute to neurogenesis and has been strongly linked to tumor suppression. Currently, little is known regarding the molecular mechanisms by which CHD5 contributes to neurogenesis or tumor suppression. We hypothesize that loss of CHD5 contributes to development of neuroblastoma because neural precursor cells lacking CHD5 fail to alter some aspect of their neural precursor transcriptome/epigenome. To study the biochemical properties and functional importance of CHD5 remodelers, we have developed a zebrafish model to study Chd5, the zebrafish homolog of human CHD5.Using the CRISPR/Cas9 system, we have engineered chd5 knockout zebrafish embryos. These zebrafish did not display any overt developmental phenotypes, however next‐generation sequencing of brain tissue from zebrafish embryos reveals that loss of chd5 is associated with broad changes in gene expression. These genes are both up and down regulated, suggesting Chd5 is necessary for both activation and repression of genes during brain development in zebrafish. Analysis of these genes and of their possible contribution to Chd5‐dependent phenotypes is underway.Support or Funding InformationPurdue Center for Cancer Research; Purdue College of Agriculture