Integration of cardiac transcription function by chromatin remodeling complexes

J. David Gladstone Institutes, San Francisco CA

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Abstract

Congenital heart defects (CHDs) are among the most common and most devastating birth defects in humans, occurring in about 1% of live births and resulting in significant mortality and morbidity. We have very little understanding ofthe processes that, when gone awry, cause CHDs. Mutations in cardiac transcription factor genes cause CHDs in humans. The cardiac transcription program must be precisely regulated, but a significant gap in our knowledge of transcription factor function is the set of interacting proteins that modulate their activity. Elucidating these interaction networks and their function is critical for an understanding of CHDs. The function of transcription factors is intimately related to and regulated by the status of the chromatin at their target binding sites, and previous work has shown that chromatin remodeling complexes interact with cardiac transcription factors. We hypothesize that Baf60c and BAF chromatin remodeling complexes play critical roles to integrate cardiac transcription factors in active regulation of crucial aspects of cardiac morphogenesis and lineage decisions. We will test this hypothesis in three Specific Aims: Specific Aim 1. To uncover the molecular network of Baf60c- and BAF complex- interacting proteins. We will define the physical interaction network between Baf60c and Its interacting partners, using an unbiased in vivo proteomics approach. Specific Aim 2. To elucidate the genomic basis for BAF complex function. We will define the genomic targets of Baf60c and Brg1, in relation to their interacting network of transcripfional co-regulators. Specific Aim 3. To determine the molecular basis for gene-specific regulation by the cardiac BAF complexes in heart morphogenesis. We will define molecular genetic pathways regulated by Baf60c and Brg1. In particular, we will identify mechanisms by which Brg1 recruitment via Baf60c and their Interaction partners activates target gene expression. The knowledge generated from this study will be crucial to our understanding ofthe mechanisms underlying CHDs.