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Review
. 2012 Jun;241(6):1021-33.
doi: 10.1002/dvdy.23796. Epub 2012 May 8.

Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins

Q Tian Wang  1
Affiliations
Review

Epigenetic regulation of cardiac development and function by polycomb group and trithorax group proteins

Q Tian Wang. Dev Dyn. 2012 Jun.

Abstract

Heart disease is a leading cause of death and disability in developed countries. Heart disease includes a broad range of diseases that affect the development and/or function of the cardiovascular system. Some of these diseases, such as congenital heart defects, are present at birth. Others develop over time and may be influenced by both genetic and environmental factors. Many of the known heart diseases are associated with abnormal expression of genes. Understanding the factors and mechanisms that regulate gene expression in the heart is essential for the detection, treatment, and prevention of heart diseases. Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are special families of chromatin factors that regulate developmental gene expression in many tissues and organs. Accumulating evidence suggests that these proteins are important regulators of development and function of the heart as well. A better understanding of their roles and functional mechanisms will translate into new opportunities for combating heart disease.

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Figures

Figure 1
Figure 1. Eukaryotic genomic DNA is packaged into chromatin
(A) Nucleosomes are the basic subunits of chromatin. Each nucleosome consists of ~146 bp of DNA wrapped approximately twice around a histone octamer (the individual monomers and histone tails are not shown). ATP-dependent chromatin remodeling can change nucleosome density, the position of nucleosome(s), nucleosome-DNA affinity, and the integrity of nucleosome(s). (B) Major modification sites on histone H3 tail. Different modifications have different effects on chromatin structure and transcriptional activity. For example, methylation of K4 and K27 is associated with transcriptionally active and silent chromatin, respectively. Modification of one residue can also promote or inhibit the modification of another residue. For example, methylation of K9 and phosphorylation of S10 inhibits each other.
Figure 2
Figure 2. Regulation of Hox genes expression by PcG and TrxG genes in Drosophila
(A) Staggered expression of Drosophila Hox genes along the anterior-posterior axis of the embryo. The Drosophila genome contains seven Hox genes arranged in two clusters: the Antennapedia complex and the Bithorax complex. The genes and their respective expression domains in the Drosophila embryo are color-coded in this diagram. Ant: anterior; Post: posterior. (B) PcG genes are required to repress Hox genes outside their normal expression domains. The diagram shows expression domain of the Hox gene AbdB in wild-type (left) vs. Pc−/− (right) embryos. AbdB is normally expressed in the posterior segments of wild-type embryos but expands anteriorly in Pc−/− embryos. (C) TrxG genes are required to maintain Hox gene expression. The diagram shows expression of the Hox gene Ubx in wild-type (left) vs. trx−/− embryos (right). Ubx expression is greatly reduced in trx−/− embryos.
Figure 3
Figure 3. PcG and TrxG proteins function at the level of chromatin
(A) Biochemical functions of the PcG complexes PRC2 and PRC1. PRC2 mediates the trimethylation of histone H3K27, a repressive histone mark. PRC1 binds H3K27me3 and compacts chromatin. (B) Biochemical functions of TrxG complexes MLL and BAF. MLL mediates trimethylation of histone H3K4. BAF has chromatin remodeling activity.
Figure 4
Figure 4. Multiple steps of cardiac development require PcG/TrxG function
Precardiac mesoderm give rise to cardiac progenitors in the first heart field (FHF) and second heart field (SHF, also known as anterior heart field or AHF). The TrxG protein Baf60c likely regulates the induction of cardiac fate. Cells in the FHF form the linear heart tube, which gives rise to the bulk of the left ventricle (LV) and also serves as a scaffold for subsequent heart growth. As the heart tube loops, cells in the SHF migrate to join the linear heart tube and give rise to the outflow tract (O), right ventricle (RV) and atria (A). Both Baf60c and the PcG protein Phc1 have been shown to regulate this early phase of cardiac development. The formation of the chambered heart from the looped heart involves a number of morphogenic processes such as trabeculation, proliferation and septation. Multiple PcG and TrxG proteins, including Brg1, Baf60c, Ezh2, Eed and Jmj, have been shown to regulate these processes. The dashed line between Jmj and Ezh2/Eed represents possible functional interaction. In addition to the FHF and SHF, cells from cardiac neural crest and proepicardium also contribute to the heart (not diagrammed).
Figure 5
Figure 5. Roles of Ezh2, Brg1 and Jmj in cardiomyocyte proliferation and trabeulation
(A) Pathways by which Ezh2, Brg1 and Jmj regulate fetal cardiomyocyte proliferation. Cyclins (such as cyclin D) activates cyclin-dependent kinases (such as Cdc4), which phosphorylate Rb and relieve Rb repression of a number of genes essential for cell cycle progression. Ezh2 promotes fetal cardiomyocyte proliferation by direct repression of the cyclin-dependent kinase inhibitor Ink4a/b. Brg1 also promotes fetal cardiomyocyte proliferation, and it does so by activating Bmp10, which in turn represses another cyclin-dependent kinase inhibitor p57kip2. Jmj inhibits fetal cardiomyocyte proliferation by repressing cyclin D and by acting as a co-repressor for Rb. It is unclear whether Jmj and Ezh2 functionally interact with each other in the repression of cyclin D and Ink4a/b, and if they do, whether Jmj promotes or inhibits PRC2 activity in these contexts (hence dashed line between Jmj and Ezh2). Over-proliferation of fetal cardiomyocytes may result in delayed differentiation. (B) Regulation of trabeculation by Ezh2, Brg1 and Jmj. The diagram shows a trabecula. Formation of these finger-like trabeculae is induced by signaling between the endocardium and the myocardium. Proteoglycans in the cardiac jelly modulates the trabeculation process by modulating the function of signaling molecules (x). Ezh2 expression in the myocardium is required for trabeculation, possibly by repressing an as-yet unidentified downstream effector (y). Brg1 expression in the endocardium promotes termination of trabeculation by activating the secreted proteinase ADAMTS1, which mediates the degradation of extracellular proteoglycans. Jmj expression in the endocardium negatively regulates trabeculation by repressing Notch.
Figure 6
Figure 6. Opposing roles of Ezh2 and Brg1 in the regulation of hypertrophic response
The adult heart responds to stress, such as pressure overload or β-adrenergic stimulation, by hypertrophic growth of cardiomyocytes. This results in thickened myocardial walls and smaller ventricular chamber(s). The PcG protein Ezh2 represses cardiac hypertrophy through a Six1-dependent pathway. The TrxG protein Brg1 is required for development of the hypertrophic response.
Figure 7
Figure 7. Known interactions between PcG/TrxG proteins and cardiac transcription factors
The TrxG complex BAF physically interacts with cardiac transcription factors GATA4, Nkx2.5 and Tbx5 and potentiates their activity on target promoters. A genetic interaction between Brg1 and the transcription factor Tbx20 has been shown, but it is unclear whether Tbx20 physically interacts with Brg1, Baf60c, or other subunit(s) of BAF. GATA4 also physically interacts with the PcG protein Ezh2, which methylates GATA4 and inhibits its activity. Jmj interacts with both GATA4 and Nkx2.5 and inhibits their activities through an as-yet unknown mechanism.
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