Abstract
Tat-interactive protein 60 (Tip60) is a member of the MYST family of histone acetyltransferases (HATs). In addition to its HAT domain, Tip contains a heterochromatin-associated protein 1-like chromodomain and a zinc finger-like domain. Several alternative splice variants of Tip60 have been characterized, including full-length Tip60alpha, Tip60beta (which lacks exon V encoded by the Tip60 gene), and Tip55 (which encodes a novel 103-amino-acid C terminus). We report here that isoproteins recognized by a pan-Tip60 antibody are strongly and transiently expressed between embryonic days 8 and 11 in the embryonic mouse myocardium. A functional role for Tip60 isoproteins in cardiac myocyte differentiation is suggested by immunoprecipitation experiments showing that Tip60alpha, Tip60beta, and Tip55 can bind serum response factor (SRF) and by transient transfection assessments showing that Tip60 and SRF cooperatively activate the atrial natriuretic factor promoter. Although this combinatorial activity is inhibited by histone deacetylase 7, it was unexpectedly enhanced by point mutation of the HAT domain. Ablation of the chromodomain from Tip60beta caused derepression. These findings suggest that Tip60 modulates expression of SRF-dependent cardiac genes.
Highlights
Co-activator or co-repressor appears to be context-dependent
Note that Tat-interactive protein 60 (Tip60) isoproteins were detected in the cytosol and nucleus of myocardial cells (Fig. 1L) as early as embryonic day 8, after which specificity and robustness of expression became pronounced through embryonic day 11 (Fig. 1C)
Tip60 Isoproteins Bind serum response factor (SRF)—Results from Fig. 1 (revealing the robust presence of Tip60 in developing myocardium, plus our results, as well as those reported by others [5, 10] showing that GAL4tethered Tip60 has little if any intrinsic activity when bound to a heterologous promoter) raised the possibility that Tip60 regulates cardiac gene transcription in cooperation with binding partners
Summary
Co-activator or co-repressor appears to be context-dependent. For example, Tip60 co-activates transcription with human immunodeficiency virus-1 Tat [1], androgen receptor [5, 6], and -amyloid precursor protein-Fe65 complex [7]. Tip60 Isoproteins Bind SRF—Results from Fig. 1 (revealing the robust presence of Tip60 in developing myocardium, plus our results (not shown), as well as those reported by others [5, 10] showing that GAL4tethered Tip60 has little if any intrinsic activity when bound to a heterologous promoter) raised the possibility that Tip60 regulates cardiac gene transcription in cooperation with binding partners.
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