PgmNr Z6113: Regulation of brain and heart development in zebrafish by the autism risk factor CHD8.

Authors:
J. A. Tracy; G. Kunkel


Institutes
Texas A&M University, College Station, TX.


Abstract:

Accessibility of the transcription machinery to regulatory elements upstream of genes is reliant on the location and stability of nucleosomes within the section of DNA. Remodeling these regions to allow binding of transcriptional regulators depends on the ATP-dependent movement of nucleosomes within the chromatin structure. The focus of this work is the ATP-dependent chromodomain helicase DNA-binding protein 8 (CHD8). CHD8 interacts with several factors that are relevant to the regulation of transcription and modulation of expression of genes implicated in crucial developmental processes and mutations within CHD8 have in multiple patients with autistic spectrum disorder. In addition to chromatin remodeling, CHD8 contains an A-kinase anchoring protein (AKAP) domain. AKAP proteins anchor protein kinase A (PKA), a kinase activated the pathway of gene regulation, to subcellular structures, thus allowing for spatial control and specialization of the PKA phosphorylation. Defects in AKAPs lead to various types of heart disease. Through the use of morpholino oligonucleotides and CRISPR/Cas9 to disrupt CHD8 expression, we have determined that CHD8 necessary for proper brain and heart development in zebrafish embryos. Reduction in CHD8 leads to disruption of expression patterns of several genes known to in brain and heart development. There are at least two isoforms of CHD8 that result from alternative splicing, and CHD8L. Interestingly, while CHD8S lacks the essential helicase domain required for nucleosome remodeling, we have that both isoforms of CHD8 are capable of activating gene expression at a ZNF143 targeted promoter but during zebrafish development.



ZFIN Genetics Index
1. chd8