Anin vivo analysis of transcriptional elements in the mouse α-myosin heavy chain gene promoter
Tóm tắt
During development in the murine ventricle, there is a switch in myosin heavy chain gene (MyHC) transcription. The β-MyHC is expressed in the ventricles during foetal development, but is shut down at or around birth, at which time α-MyHC transcription is activated. This antithetical switch is thought to be mediated by circulating levels of thyroid hormone (TH) and both low and high affinity thyroid response elements (TREs) have been identified in the proximal promoter region of the murine α-MyHC. Myosin gene expression in the atria is relatively unaffected by the TH status. Previously, we used site-directed mutagenesis of the promoter in a transgenic analysis to define those elements responsible for high levels of transcriptionin vivo. These analyses focused on the role(s) of twocis elements, TRE1 and TRE2 that are located at −129 to −149 and −102 to −120, respectively, on the α-MyHC promoter. Although the elements' ablation had differential effects on transgene expression, neither single mutation abolished transgene expression completely. Here, we show that mutating both elements results in a complete inactivation of the transgene in both ventricles and atria under euthyroid conditions. However, expression still can be detected in the hyperthyroid state, implying that, although the TRE1 and TRE2 elements are critical elements for high levels of α-MyHC transcriptionin vivo, other promoter sites can mediate at least some degree of transcriptional activation.
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