Thursday, May 2, 2024
5/2/2024
PROJECT SUMMARY GATA zinc finger domain containing 1 (GATAD1) is an as-yet uncharacterized zinc finger domain protein, which was initially identified as a histone 3 trimethylated at lysine 4 (H3K4me3) interactor. Genome-wide homozygosity mapping and exome sequencing identified a GATAD1 mutation in a large four-generation family with autosomal recessive dilated cardiomyopathy (DCM). Three individual carriers homozygous for a single amino acid substitution of Serine 102 to Proline (S102P) in GATAD1 presented with full penetrance adult-onset DCM and heart failure in their fifties. However, thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages. The unique DCM phenotype observed in patients homozygous for the S102P mutation and the absence of symptoms in heterozygous carriers suggest that the S102P mutation is a loss-of-function mutation, and that GATAD1 is critical for maintaining normal cardiac structure and function. However, little is known as to the specific role of GATAD1 in CMs, or molecular mechanisms by which GATAD1 loss-of-function results in cardiomyopathy. Gatad1 knockout zebrafish display a heart failure-like phenotype and lethality at 7 months of age when exposed to ethanol and high cholesterol stress. GATAD1 interacts with H3K4me3 and binds at gene promoters, suggesting it is likely to regulate gene expression. However, the transcriptional program regulated by GATAD1 in CMs has not yet been addressed. To determine the role of GATAD1 in CMs, we have successfully generated a floxed Gatad1 mouse line and used it to generate CM-specific knockout (cKO) mice. Our preliminary studies revealed that, although the cardiac structure and function were normal in in Gatad1 cKO mice at 3 months of age, expression of fetal genes Nppa and Nppb, typically upregulated during cardiac stress, were increased in hearts of Gatad1 cKO mice, compared with those of Cre negative controls, suggesting that deletion of Gatad1 in CMs induced cardiac stress. The normal cardiac function in Gatad1 cKO mice at 3 months of age suggests that loss of Gatad1 might result in slowly developing late-onset cardiomyopathy during aging, as observed in the patients carrying GATAD1 mutations. Interestingly, we observed that expression of Gatad1, was increased in hearts one week after pressure overload. Taken together, the foregoing evidence leads us to the hypothesis that GATAD1 plays an essential role in maintaining normal cardiac function and in response to cardiac stress by regulating cardiac gene expression. Accordingly, our Specific Aims are: (1) To elucidate the role and molecular mechanism by which GATAD1 is required to maintain normal cardiac function during aging by histological, physiological, biochemical, and molecular analyses of Gatad1 CM-specific knockout (cKO) mice. and (2) To investigate the role of GATAD1 in pressure-overload induced heart failure by preforming transverse aortic constriction (TAC) surgery on Gatad1 cKO mice at two months of age, prior to any cardiac phenotype.
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