Tbx1 represses Mef2c gene expression and is correlated with histone 3 deacetylation of the anterior heart field enhancer

Abstract

The 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.

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

“…Additionally, TBX1, a transcription factor located in the 22q11.2 deletion region and significantly downregulated in these same NPCs (Extended Data Fig. 2d,e), is a known repressor of MEF2C 49,50 . Thus, decreased TBX1 levels due to loss of a copy of 22q11.2 likely result in de-repression of the MEF2C transcription factor, a regulator of the JUN/FOS signaling pathway, which in turn might reduce synaptic transmission.…”

“…In neurons, the deletion alters activity-dependent gene expression, protein homeostasis and ultimately, presynaptic biology. Overall, it was notable that MEF2C, an activity dependent transcription factor and negative regulator of excitatory synaptic density 66,67 is overexpressed in NPCs with 22q11.2 deletion, likely due to the loss of one copy of TBX1, a known MEF2C inhibitor located in the 22q11.2 interval 49,50 . Increased expression of MEF2C, could, in turn, lead to premature activation of the JUN and FOS pathway, which would be predicted to result in reduced network activity and synaptic connectivity.…”

“…We took particular note of MEF2C as it is also implicated in schizophrenia through GWAS and is known to encode a transcriptional regulator that participates in activity-dependent regulation of immediate early genes such as JUN and FOS 48 . MEF2C has been shown to be repressed by the transcription factor TBX1, which is encoded by a gene within the 22q11.2 interval 49,50 .…”

Heart Enhancers: Development and Disease Control at a Distance

“…E1: exon 1. These schematics are generated based on data from these publications: mouse Nkx2.5 ( Searcy et al, 1998 ; Lien et al, 1999 , 2002 ; Liberatore et al, 2002 ; Brown et al, 2004 ; Chi et al, 2005 ; Takeuchi et al, 2005 ; Chen and Cao, 2009 ; Clark et al, 2013 ; Doppler et al, 2014 ; Quinodoz et al, 2018 ); Chicken NKX2.5 ( Lee et al, 2004 ); Mouse Gata4 ( Rojas et al, 2005 ; Schachterle et al, 2012 ); zebrafish gata4 ( Heicklen-Klein and Evans, 2004 ); mouse Gata6 ( Molkentin et al, 2000 ); Chicken GATA6 ( He and Burch, 1997 ; Davis et al, 2001 ; Adamo et al, 2004 ); mouse Mef2c ( Dodou et al, 2004 ; Takeuchi et al, 2005 ; Pane et al, 2018 ); mouse Hand2 ( McFadden et al, 2000 ).…”

“…For example, the lateral mesoderm expression of mouse Gata4 relies on transcriptional inputs from FOXF1, BMP4, and its autoregulation ( Rojas et al, 2005 ), while its expression in endocardia requires binding of ETS factors such as ETS1 and ERG ( Schachterle et al, 2012 ). The anterior heart field (AHF) expression of Mef2c is positively regulated by GATA4, ISL1, and TBX20 and repressed by TBX1 through an intronic enhancer ( Dodou et al, 2004 ; Takeuchi et al, 2005 ; Pane et al, 2018 ). Ventricular expression of Hey2 is dependent on TBX20 and GATA factor binding, but not NK-2 proteins.…”