Regulation of cardiac patterning via Akirin/NuRD Interactions

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Project Summary Congenital heart defects are the most prevalent birth defects in the human population, with an incident rate as high as 10 in 1000 live births. A significant number of these cases are termed sporadic, which are largely the result of interactions between a number of independent genetic loci and alleles. To aid in our understanding of the polygenic nature of congenital heart defects, it remains imperative to continue to identify new gene regulatory partners that may play a role in the process of embryonic heart patterning. Our laboratory has recently identified a cofactor, Akirin, that is responsible for interfacing transcription factor activity with chromatin remodeling machinery to facilitate gene expression. Importantly, Akirin appears to play a role in the proper patterning and morphogenesis of the embryonic heart in Drosophila melanogaster. Excitingly, our preliminary data suggests that Akirin likely regulates insect embryonic heart development through interactions with the CHD4/NuRD family of chromatin remodeling machinery. This mechanism of Akirin/NuRD interactions for expression of cardiac developmental gene pathways appears to be conserved from mammals to insects. To further determine the role of Akirin/NuRD interactions in the process of heart development, we propose two specific aims: 1) Using a combination of genetic, biochemical, and live imaging techniques, will confirm the importance of Akirin/NuRD interactions during development, and 2) We will employ both next-generation massively parallel RNA sequencing methods, as well as ATAC-seq and conventional chromatin immunoprecipitation methods to determine the gene regulatory role of Akirin during cardiac myogenesis. This work will provide key data for understanding the role of Akirin in the process of heart formation, and provide a new avenue for studying and/or preventing causes of congenital heart defects. Critically, in keeping with the goals of the AREA award mechanism, this project will give undergraduate researchers hands-on experience in a wide variety of molecular, genetic, histological, microscopic, and biochemical techniques, which will provide a valuable skill set for a future career in biomedical research.