Dataset Information

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

ABSTRACT: Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC10354062 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Zhao Yingjie Y Wang Yujue Y Shi Lijie L McDonald-McGinn Donna M DM Crowley T Blaine TB McGinn Daniel E DE Tran Oanh T OT Miller Daniella D Lin Jhih-Rong JR Zackai Elaine E Johnston H Richard HR Chow Eva W C EWC Vorstman Jacob A S JAS Vingerhoets Claudia C van Amelsvoort Therese T Gothelf Doron D Swillen Ann A Breckpot Jeroen J Vermeesch Joris R JR Eliez Stephan S Schneider Maude M van den Bree Marianne B M MBM Owen Michael J MJ Kates Wendy R WR Repetto Gabriela M GM Shashi Vandana V Schoch Kelly K Bearden Carrie E CE Digilio M Cristina MC Unolt Marta M Putotto Carolina C Marino Bruno B Pontillo Maria M Armando Marco M Vicari Stefano S Angkustsiri Kathleen K Campbell Linda L Busa Tiffany T Heine-Suñer Damian D Murphy Kieran C KC Murphy Declan D García-Miñaúr Sixto S Fernández Luis L Zhang Zhengdong D ZD Goldmuntz Elizabeth E Gur Raquel E RE Emanuel Beverly S BS Zheng Deyou D Marshall Christian R CR Bassett Anne S AS Wang Tao T Morrow Bernice E BE

NPJ genomic medicine 20230718 1

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may ...[more]

PMID: 37463940

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Project description:BackgroundTBX1 (T-box transcription factor 1) is a major candidate gene that likely contributes to the etiology of velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS). Although the haploinsufficiency of TBX1 in both mice and humans results in congenital cardiac malformations, little has been elucidated about its upstream regulation. We aimed to explore the transcriptional regulation and dysregulation of TBX1.MethodsDifferent TBX1 promoter reporters were constructed. Luciferase assays and electrophoretic mobility shift assays (EMSAs) were used to identify a cis-regulatory element within the TBX1 promoter region and its trans-acting factor. The expression of proteins was identified by immunohistochemistry and immunofluorescence. Variants in the cis-regulatory element were screened in conotruncal defect (CTD) patients. In vitro functional assays were performed to show the effects of the variants found in CTD patients on the transactivation of TBX1.ResultsWe identified a cis-regulatory element within intron 1 of TBX1 that was found to be responsive to GATA6 (GATA binding protein 6), a transcription factor crucial for cardiogenesis. The expression patterns of GATA6 and TBX1 overlapped in the pharyngeal arches of human embryos. Transfection experiments and EMSA indicated that GATA6 could activate the transcription of TBX1 by directly binding with its GATA cis-regulatory element in vitro. Furthermore, sequencing analyses of 195 sporadic CTD patients without the 22q11.2 deletion or duplication identified 3 variants (NC_000022.11:g.19756832C > G, NC_000022.11:g.19756845C > T, and NC_000022.11:g. 19756902G > T) in the non-coding cis-regulatory element of TBX1. Luciferase assays showed that all 3 variants led to reduced transcription of TBX1 when incubated with GATA6.ConclusionsOur findings showed that TBX1 might be a direct transcriptional target of GATA6, and variants in the non-coding cis-regulatory element of TBX1 disrupted GATA6-mediated transactivation.

Dataset Information

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Publications

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

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