35Tbx1 functions and chromatin

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Abstract

The T-Box transcription factor Tbx1 is expressed in the second heart field and regulates several important aspects of cardiac outflow tract (OFT) development and pharyngeal apparatus development. Like other tissue-specific transcription factors, it must function in the context of DNA assembled into the higher-order structure of chromatin. Here we show the interaction between Tbx1 and a specific subunit of the Swi/Snf-like BAF complex. We speculate that this interaction promotes the rearrangement of the chromatin to facilitate access of the transcriptional machinery to Tbx1 target genes. We identified a novel and important transcriptional target of Tbx1: Wnt5a, a gene encoding for a ligand of the non canonical Wnt pathway. Our data suggest that Tbx1 recruits Baf60a, a subunit of the BAF chromatin remodeling complex associated with undifferentiated/multipotent status, onto the Wnt5a gene. Furthermore, we found a physical interaction with the histone methyltransferase Setd7 and the enrichment of H3K4 monomethylation status on the target loci after Tbx1 over-expression, resulting in transcriptional enhancement of the target gene. To analyze the functional significance of such regulation we focused on genetic interaction in-vivo.

Since both Tbx1 and Wnt5a genes are expressed in the second heart field (SHF) and mutations of Wnt5a have been found in patients with cardiac outflow tract defects, we investigated their potential interaction. We found that reduced dosage of Wnt5a enhances the Tbx1 haploinsufficiency phenotype, and that haploinsufficiency of Tbx1 enhances the Wnt5a null phenotype. In addition, combined loss of Tbx1 and Wnt5a caused severe hypoplasia of SHF-derived heart segments and early embryonic lethality. This is a much more severe phenotype than that caused by loss of the individual genes, suggesting that the two genes function in two interacting but distinct pathways essential for SHF development: The Wnt5a-Ror2 pathway is known to be implicated in oriented cell migration in several developmental contexts while Tbx1 regulates proliferation and differentiation in the SHF. We also found an up-regulation of Beta-catenin expression in the double mutants suggesting an interference with the Wnt canonical signaling in the SHF that could led to the heart abnormalities observed.

Overall our data suggest a model in which Tbx1 regulates Wnt5a in cardiac precursor cells by recruiting a chromatin remodeling machinery and a histone modifying enzyme that facilitates gene transcription. This may be a general mechanism for Tbx1 function in cardiac progenitors.

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