CAMTA: A Signal-Responsive Transcription Factor That Promotes Cardiac Growth by Opposing Class II Histone Deacetylases
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Cardiac growth is finely regulated by transcriptional circuits. In an effort to discover new regulators of cardiac growth, I performed a eukaryotic expression screen for activators of the atrial natriuretic factor (ANF) gene, a cardiac-specific marker of hypertrophic signaling and embryonic development. I discovered that a family of transcription factors, called CAMTAs, regulate the ANF promoter. CAMTA proteins were first discovered in plants, however, little was known of the mechanism of their action and biological function and virtually nothing was known about mammalian CAMTA proteins, CAMTA1 and CAMTA2. CAMTA1 and CAMTA2 are enriched in embryonic and adult hearts, skeletal muscle at the embryonic stage, and brain. To define the mechanism whereby CAMTA2 activates the ANF promoter, I used a series of promoter deletion mutants to map the cis-regulatory sequences that confer responsiveness to CAMTA2. I found that CAMTA activates the ANF gene, at least in part, by associating with Nkx2-5, a cardiac transcription factor. CAMTA proteins also activate promoters of myogenin and beta myosin heavy chain via direct DNA binding. Therefore, CAMTAs activate target genes through diverse mechanisms. Over-expression of CAMTA2 in vitro and in vivo promotes cardiac growth. Based on the ability of CAMTA2 to induce hypertrophy, I tested whether signaling molecules implicated in cardiac hypertrophy might enhance the activity of CAMTA2. I discovered that the transcriptional activity of CAMTAs is governed by association with class II histone deacetylases (HDACs), which negatively regulate cardiac growth. Mice homozygous for a mutation in the CAMTA2 gene are defective in cardiac growth in response to pressure overload and neurohumoral signaling, whereas mice lacking HDAC5, a class II HDAC are sensitized to the pro-hypertrophic actions of CAMTA. CAMTA proteins are also required for embryonic heart development, as demonstrated by heart defects in mice with low dosage of CAMTA1. These findings reveal a transcriptional regulatory mechanism that modulates cardiac growth and gene expression by linking cardiac growth signals to the cardiac genome.