Dual Transcriptional Activator and Repressor Roles of TBX20 Regulate Adult Cardiac Structure and Function

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2012 Feb 14

PMID 22328084

Citations 49

Authors

Noboru J Sakabe

Ivy Aneas

Tao Shen

Leila Shokri

Soo-Young Park

Martha L Bulyk

Sylvia M Evans

Marcelo A Nobrega

Affiliations

Soon will be listed here.

Abstract

The ongoing requirement in adult heart for transcription factors with key roles in cardiac development is not well understood. We recently demonstrated that TBX20, a transcriptional regulator required for cardiac development, has key roles in the maintenance of functional and structural phenotypes in adult mouse heart. Conditional ablation of Tbx20 in adult cardiomyocytes leads to a rapid onset and progression of heart failure, with prominent conduction and contractility phenotypes that lead to death. Here we describe a more comprehensive molecular characterization of the functions of TBX20 in adult mouse heart. Coupling genome-wide chromatin immunoprecipitation and transcriptome analyses (RNA-Seq), we identified a subset of genes that change expression in Tbx20 adult cardiomyocyte-specific knockout hearts which are direct downstream targets of TBX20. This analysis revealed a dual role for TBX20 as both a transcriptional activator and a repressor, and that each of these functions regulates genes with very specialized and distinct molecular roles. We also show how TBX20 binds to its targets genome-wide in a context-dependent manner, using various cohorts of co-factors to either promote or repress distinct genetic programs within adult heart. Our integrative approach has uncovered several novel aspects of TBX20 and T-box protein function within adult heart. Sequencing data accession number (http://www.ncbi.nlm.nih.gov/geo): GSE30943.

Citing Articles

Chromosomal Location and Identification of as a New Gene Responsible for Familial Bicuspid Aortic Valve.

Li Y, Zou S, Bian Y, Liu X, Yang C, Li L Diagnostics (Basel). 2025; 15(5).

PMID: 40075846 PMC: 11898536. DOI: 10.3390/diagnostics15050600.

Role of Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

Amor-Salamanca A, Santana Rodriguez A, Rasoul H, Rodriguez-Palomares J, Moldovan O, Hey T Circ Genom Precis Med. 2024; 17(2):e004404.

PMID: 38353104 PMC: 11019988. DOI: 10.1161/CIRCGEN.123.004404.

Transcriptome analysis of human hypertrophic cardiomyopathy reveals inhibited cardiac development pathways in children.

Chen S, Hu J, Xu Y, Yan J, Li S, Chen L iScience. 2024; 27(1):108642.

PMID: 38205249 PMC: 10777066. DOI: 10.1016/j.isci.2023.108642.

Discovery of as a Novel Gene Underlying Atrial Fibrillation.

Li N, Li Y, Guo X, Wu S, Jiang W, Zhang D Biology (Basel). 2023; 12(9).

PMID: 37759586 PMC: 10525918. DOI: 10.3390/biology12091186.

The Tbx20-TLE interaction is essential for the maintenance of the second heart field.

Edwards W, Bussey O, Conlon F Development. 2023; 150(21).

PMID: 37756602 PMC: 10629681. DOI: 10.1242/dev.201677.

References

Taher L, Ovcharenko I . Variable locus length in the human genome leads to ascertainment bias in functional inference for non-coding elements. Bioinformatics. 2009; 25(5):578-84. PMC: 2647827. DOI: 10.1093/bioinformatics/btp043. View

Lopaschuk G, Jaswal J . Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol. 2010; 56(2):130-40. DOI: 10.1097/FJC.0b013e3181e74a14. View

Liu C, Shen A, Li X, Jiao W, Zhang X, Li Z . T-box transcription factor TBX20 mutations in Chinese patients with congenital heart disease. Eur J Med Genet. 2008; 51(6):580-7. DOI: 10.1016/j.ejmg.2008.09.001. View

Bryne J, Valen E, Tang M, Marstrand T, Winther O, da Piedade I . JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res. 2007; 36(Database issue):D102-6. PMC: 2238834. DOI: 10.1093/nar/gkm955. View

Luo J, Wu S, Liu J, Li Y, Yang H, Kim T . Conditional PPARγ knockout from cardiomyocytes of adult mice impairs myocardial fatty acid utilization and cardiac function. Am J Transl Res. 2010; 3(1):61-72. PMC: 2981426. View

Posch M, Gramlich M, Sunde M, Schmitt K, Lee S, Richter S . A gain-of-function TBX20 mutation causes congenital atrial septal defects, patent foramen ovale and cardiac valve defects. J Med Genet. 2009; 47(4):230-5. PMC: 2981023. DOI: 10.1136/jmg.2009.069997. View

McLean C, Bristor D, Hiller M, Clarke S, Schaar B, Lowe C . GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010; 28(5):495-501. PMC: 4840234. DOI: 10.1038/nbt.1630. View

Frith M, Fu Y, Yu L, Chen J, Hansen U, Weng Z . Detection of functional DNA motifs via statistical over-representation. Nucleic Acids Res. 2004; 32(4):1372-81. PMC: 390287. DOI: 10.1093/nar/gkh299. View

Holm H, Gudbjartsson D, Arnar D, Thorleifsson G, Thorgeirsson G, Stefansdottir H . Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet. 2010; 42(2):117-22. DOI: 10.1038/ng.511. View

10.

Chong J, Tapia-Ramirez J, Kim S, Toledo-Aral J, Zheng Y, Boutros M . REST: a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell. 1995; 80(6):949-57. DOI: 10.1016/0092-8674(95)90298-8. View

11.

Miller S, Huang A, Miazgowicz M, Brassil M, Weinmann A . Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev. 2008; 22(21):2980-93. PMC: 2577798. DOI: 10.1101/gad.1689708. View

12.

Sotoodehnia N, Isaacs A, de Bakker P, Dorr M, Newton-Cheh C, Nolte I . Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. 2010; 42(12):1068-76. PMC: 3338195. DOI: 10.1038/ng.716. View

13.

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

14.

Berger J, Akiyama T, Meinke P . PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci. 2005; 26(5):244-51. DOI: 10.1016/j.tips.2005.03.003. View

15.

Edgar R, Domrachev M, Lash A . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2001; 30(1):207-10. PMC: 99122. DOI: 10.1093/nar/30.1.207. View

16.

Macindoe I, Glockner L, Vukasin P, Stennard F, Costa M, Harvey R . Conformational stability and DNA binding specificity of the cardiac T-box transcription factor Tbx20. J Mol Biol. 2009; 389(3):606-18. DOI: 10.1016/j.jmb.2009.04.056. View

17.

Newburger D, Bulyk M . UniPROBE: an online database of protein binding microarray data on protein-DNA interactions. Nucleic Acids Res. 2008; 37(Database issue):D77-82. PMC: 2686578. DOI: 10.1093/nar/gkn660. View

18.

Siepel A, Bejerano G, Pedersen J, Hinrichs A, Hou M, Rosenbloom K . Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005; 15(8):1034-50. PMC: 1182216. DOI: 10.1101/gr.3715005. View

19.

Pruitt K, Tatusova T, Klimke W, Maglott D . NCBI Reference Sequences: current status, policy and new initiatives. Nucleic Acids Res. 2008; 37(Database issue):D32-6. PMC: 2686572. DOI: 10.1093/nar/gkn721. View

20.

Schoenherr C, Anderson D . The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science. 1995; 267(5202):1360-3. DOI: 10.1126/science.7871435. View