Down-regulation of EBAF in the heart with ventricular septal defects and its regulation by histone acetyltransferase p300 and transcription factors smad2 and cited2

Abstract

As a NODAL pathway inhibitor, EBAF plays a critical role during mammalian cardiac development. As recent tests that have been conducted on gene-targeted mice indicate, its expression is frequently altered where cardiac defects are present. We aimed to explore the EBAF expression pattern and molecular mechanism of EBAF gene for VSD genesis. In this report, we show that the average expression of EBAF in the disease tissues of VSD patients was lower than the expression in normal fetuses without VSD. Further study showed that the expression pattern of EBAF was potentially involved in cardiomyocyte apoptosis by Annexin-V and RT-PCR assays. We also found that abnormal activation of NODAL-PITX2C pathway was associated with down-regulation of EBAF. By luciferase reporter assays, we find that EBAF expression is mediated by transcriptional factors smad2 and cited2. In addition, ChIP assays showed that histone acetyltransferase p300 is involved in the activation of EBAF through inducing hyperacetylation of histone H4 at the EBAF promoter. Co-immunoprecipitation also indicates that the expression of EBAF is regulated by a transcriptional complex including p300, smad2, and cited2. This study revealed a novel regulator mechanism of EBAF, which may be a potential molecular target for halting the onset of VSDs. They also indicate that smad2, cited2, and p300 may play important roles in modulating the confirmation of ventricular septal defects.

Pitx2c Is Reactivated in the Failing Myocardium and Stimulates Myf5 Expression in Cultured Cardiomyocytes

“…This new observation adds an additional layer of complexity to the challenge linking perturbations of Pitx2c expression in the LA to the development of atrial fibrillation [11]. Mechanistically, the results of this study strongly suggest that Pitx2c activation is a common feature of the failing heart, in line with recent reports of myocardial Pitx2c upregulation in HF due to ventricular septal defects in human foetuses [50]. The question is whether Pitx2c upregulation deteriorates the failing myocardium as one of the factors for HF progression or its activation is merely a secondary manifestation of impaired LV function that might even have a compensatory effect in HF?…”

Genetic testing for ventricular septal defect

“…Differential diagnosis should consider VSD caused by Down syndrome and other chromosomal disorders (8,9). The vast majority of these genes are key components of the Nodal signaling pathway that is important for specification and patterning of vertebrate embryos (30) and in mammalian cardiac development (31).…”

CITED2 affects leukemic cell survival by interfering with p53 activation

“…By binding to CBP/p300, CITED2 was shown to regulate the CBP/p300-mediated transactivation of multiple transcription factors such as HIF1 α , 3 NF- κ B, 5 LHX2, 6 TFAP2, 7 MYC, 8 PPAR α 9 and SMAD2. 10 Presence of CITED2 can enhance or repress the target gene expression of these transcription factors. In case of HIF1 α and NF- κ B, CITED2 has been described to compete for p300 and thereby block HIF1 α - and NF- κ B-mediated transcription.…”