Epigenetic Factors Regulating Ventricular Development

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In addition to the DNA-binding proteins described above, there is growing evidence of epigenetic factors that are critical for ventricular morphogenesis by virtue of their ability to regulate gene expression through chro-matin remodeling events. Covalent modification of the amino-terminal tails of histones, particularly H3 and H4, regulates higher-order chromatin structure and gene expression (Fig. 3). Modifications include acetylation of specific lysine residues (e.g., lysine9 of histone H3) by histone acetyl transferases (HATs), deacetylation by his-tone deacetylases (HDACs), phosphorylation (serine10 of histone H3) by kinases and, most recently, methylation of lysine9 of histone H3 by histone methyl transferases (HMTs) (Cheung et al. 2000; Khochbin et al. 2001; Marmorstein and Roth 2001).

mBop is one such factor that is expressed specifically in cardiac and skeletal muscle during development and contains two interesting domains that promote condensation of heterochromatin, resulting in transcriptional silencing (Gottlieb et al. 2002). The mBop protein contains a MYND domain most similar to that of the ETO protein whose fusion with the AML1 protein in chronic myelogenous leukemia converts AML1, normally a transcriptional activator, into a transcriptional repressor (Lutterbach et al. 1998a, b). The MYND domain of ETO is essential for this conversion and appears to function by recruiting the nuclear co-repressor, N-CoR, which in turn recruits the Sin3/HDAC complex to DNA sites specified by AML1 binding. mBop also recruits HDACs through the MYND domain and functions as a transcriptional repressor in part through this mechanism (Gottlieb et al. 2002).

It is unique that mBop also contains a SET domain that, in other proteins, contains the catalytic domain necessary for HMT activity (Rea et al. 2000). Most of the essential residues for HMT activity are conserved in mBop, suggesting that it plays a role through regulation of the methylation state of histones. It is interesting that the lysine residues of histone tails that get methylated must first be deacetylated, raising the possibility that mBop is able

Figure 3. Schematic of epigenetic events regulating chromatin structure and transcription. Acetylation of specific lysine residues in tails of histone H3 or H4 by histone acetyl-trans-ferases (HATs) results in relaxation of chromatin structure, making target DNA more accessible to DNA-binding transcription factors. The reverse reaction is catalyzed by histone deacetylases (HDACs) and results in condensation of chromatin into a transcriptionally silent state. Deacetylated residues can be methylated by histone methyl-transferases (HMTs), causing a more permanent state of transcriptional silencing. Acetylated (Ac) or methylated (Me) residues are recognized by bromodomain (BD)- or chromodomain (CD)-containing proteins, respectively.

Figure 3. Schematic of epigenetic events regulating chromatin structure and transcription. Acetylation of specific lysine residues in tails of histone H3 or H4 by histone acetyl-trans-ferases (HATs) results in relaxation of chromatin structure, making target DNA more accessible to DNA-binding transcription factors. The reverse reaction is catalyzed by histone deacetylases (HDACs) and results in condensation of chromatin into a transcriptionally silent state. Deacetylated residues can be methylated by histone methyl-transferases (HMTs), causing a more permanent state of transcriptional silencing. Acetylated (Ac) or methylated (Me) residues are recognized by bromodomain (BD)- or chromodomain (CD)-containing proteins, respectively.

to both recruit HDACS to "prepare" specific residues, and subsequently methylate those residues.

Investigation of the in vivo function of mBop was undertaken by targeted disruption in mice (Gottlieb et al. 2002). Mouse embryos lacking mBop displayed right ventricular hypoplasia and immature ventricular car-diomyocytes (Fig. 4); surprisingly, atrial cardiomyocytes appeared to differentiate normally. This phenotype was similar but more severe than that observed in mice lacking dHAND. Consistent with this, mBop was required for dHAND expression in the precardiac mesoderm, well before right ventricular formation, suggesting that regulation of dHAND may contribute to the right ventricular hypoplasia in Bop mutants (Fig. 4). Consistent with mBop's effects on dHAND, Irx4 was also down-regulated in Bop mutants. Because mBop likely functions in vivo as a re-pressor of transcription, it is probable that there is an intermediate protein regulated by mBop that subsequently affects dHAND transcription and further downstream events. Identification of the molecular steps leading to mBop regulation of dHAND may yield insights into the precise targets to which mBop is recruited.

Other DNA-binding transcription factors also interact with HDACs and may regulate ventricular development through this mechanism. One member of the Mef2 family of transcriptional regulators, Mef2c, is essential for formation of the right and left ventricles in mice (Lin et al. 1997). Silencing of Mef2-dependent transcription through interaction with HDACs is necessary for regulation of hypertrophic growth of postnatal cardiomyocytes (McKinsey et al. 2000; Zhang et al. 2002). Whether a similar mechanism is involved in embryonic development of the heart remains unknown.

Finally, the hairy related transcription factors, Hrt1, Hrt2, and Hrt3, are expressed abundantly in the developing cardiovascular system and are transcriptional repres-sors that mediate events downstream of signaling by the

Figure 4. dHAND is down-regulated in Bop-null cardiac precursors. Transverse sections of Bop or wild-type embryos at E9.25 reveal a single left-sided ventricle (v) that abruptly connects to an outflow tract (ot) in the mutant (A, D). dHAND expression is down-regulated in E9.0 Bop-null embryos specifically in the heart compared to wild type (B, E). Lateral plate mesoderm (lpm) and pharyngeal arch (pa) expression is unaffected. At E7.75, dHAND is barely detectable in the cardiac crescent (cc) but is expressed normally in the bilateral lateral plate mesoderm compared to wild type (C, F). (e) Endocardium, (m) myocardium, (rv) right ventricle, (lv) left ventircle, (al) allantois.

Figure 4. dHAND is down-regulated in Bop-null cardiac precursors. Transverse sections of Bop or wild-type embryos at E9.25 reveal a single left-sided ventricle (v) that abruptly connects to an outflow tract (ot) in the mutant (A, D). dHAND expression is down-regulated in E9.0 Bop-null embryos specifically in the heart compared to wild type (B, E). Lateral plate mesoderm (lpm) and pharyngeal arch (pa) expression is unaffected. At E7.75, dHAND is barely detectable in the cardiac crescent (cc) but is expressed normally in the bilateral lateral plate mesoderm compared to wild type (C, F). (e) Endocardium, (m) myocardium, (rv) right ventricle, (lv) left ventircle, (al) allantois.

transmembrane receptor, Notch (Nakagawa et al. 1999, 2000). The zebrafish ortholog of Hrt2, gridlock, regulates the sorting of endothelial precursors into arterial or venous endothelial cells by mediating Notch signals (Zhong et al. 2001). In the mouse, Hrt2 transcripts are present specifically in the ventricles but not atria, suggesting a ventricular-specific role for this gene in mammals (Nakagawa et al. 1999). Recent evidence suggests that the transcriptional repression by Hrt2 is mediated in part by recruitment of HDACs (Iso et al. 2001), although the impact of ventricular-specific histone modifications mediated by Hrt2 remains unknown.

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