Abstract
ABSTRACTThe TBX1 gene is haploinsufficient in 22q11.2 deletion syndrome (22q11.2DS), and genetic evidence from human patients and mouse models points to a major role of this gene in the pathogenesis of this syndrome. Tbx1 can activate and repress transcription, and previous work has shown that one of its functions is to negatively modulate cardiomyocyte differentiation. Tbx1 occupies the anterior heart field (AHF) enhancer of the Mef2c gene, which encodes a key cardiac differentiation transcription factor. Here, we show that increased dosage of Tbx1 correlates with downregulation of Mef2c expression and reduced acetylation of its AHF enhancer in cultured mouse myoblasts. Consistently, 22q11.2DS-derived and in vitro-differentiated human induced pluripotent stem cells (hiPSCs) expressed higher levels of MEF2C and showed increased AHF acetylation, compared with hiPSCs from a healthy donor. Most importantly, we show that in mouse embryos, loss of Tbx1 enhances the expression of the Mef2c-AHF-Cre transgene in a specific region of the splanchnic mesoderm, and in a dosage-dependent manner, providing an in vivo correlate of our cell culture data. These results indicate that Tbx1 regulates the Mef2c AHF enhancer by inducing histone deacetylation.
Highlights
During development, cardiac progenitors of the second heart field (SHF) are recruited or incorporated into the cardiac outflow tract and right ventricle (Kelly et al, 2001; Mjaatvedt et al, 2001; Waldo et al, 2001)
Increased Tbx1 expression is associated with reduced histone 3 acetylation of the Mef2c anterior heart field (AHF) enhancer sequence To understand the mechanisms by which Tbx1 represses Mef2c, we used mouse myoblast C2C12 cells undergoing muscle differentiation
To exclude that this effect might be due to a delayed differentiation caused by early Tbx1 transfection, we repeated the experiment by transfecting Tbx1 after the initiation of differentiation, at day 2, and assayed Mef2c expression at day 3
Summary
Cardiac progenitors of the second heart field (SHF) are recruited or incorporated into the cardiac outflow tract and right ventricle (Kelly et al, 2001; Mjaatvedt et al, 2001; Waldo et al, 2001) During this process, cells activate a differentiation program that leads to expression of specialized proteins, such as contractile proteins necessary for cardiomyocyte function. This process, still to be dissected in detail, should be tightly regulated so that a sufficient number of progenitors are allowed to proliferate and are prevented from differentiating prematurely These two basic functions ( pro-proliferative and anti-differentiative) are likely. Downregulation of Srf and Smad signaling is effected through nontranscriptional mechanisms, but Mef2c gene expression appears to be transcriptionally repressed by Tbx
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