Abstract
The role of two putative, cis-acting thyroid hormone-responsive elements, TRE1 and TRE2, located at -129 to -149 and -102 to -120, respectively, on the murine alpha-myosin heavy chain (MHC) gene, has been investigated in transgenic mice. These motifs are present in a 4.5-kilobase fragment lying upstream of the transcriptional start site of the mouse alpha-MHC gene: this fragment directs appropriate expression of a reporter gene in transgenic mice (Subramaniam, A., Jones, W. K., Gulick, J., Wert, S., Neumann, J., and Robbins, J. (1991) J. Biol. Chem. 266, 24613-24620). Here, we independently mutate the TRE1 and TRE2 elements by base substitution. The mice were analyzed for transgene expression in different muscle and non-muscle tissues including the atria and ventricles. Normal levels of transgene expression were observed in euthyroid mice carrying a mutation in TRE1. In contrast to these results, mice in which TRE2 was mutated showed reduced levels of CAT activity in both the atria and ventricles, suggesting a previously undefined role for this element in the constitutive up-regulation of the alpha-MHC gene. In hypothyroid mice carrying either of these mutations, the complete cessation of ventricular expression of the chloramphenicol acetyltransferase transcripts that takes place in the alpha-5.5 (wild type) animals did not occur.
Highlights
The role of two putative, cis-acting thyroid hormoneresponsive elements, TREl and TRE2,located at -129 to -149and -102 to -120, respectively, on the murine a-myosin heavy chain (MHC) gene, has been investigated in transgenic mice
The two myosin heavy chain (MHC)’ genes, a and P, that are expressed in the mammalian heart are part of alarge, multigene family whose members are expressed in a muscle type- and developmental stage-specific manner [1,2,3]
There is an antithetic switch in ventricular MHC gene expression such that the /3-MHC transcripts are rapidly replaced by a-MHC RNA [1, 2, 8,9,10,11,12]
Summary
Cam, acetylated chloramphenicol; Gastro., gastrocnemius; Diaphr., diaphragm; Ventric.,ventricle; A. In lines derived from both of the constructs,high levels of CAT activity are present in the euthyroid extracAtss. Extracts derived from euthyroid, TRE-' muta ventricles show, as before, relatively low levels of CAT activity. The two other a-3 lines obtained showed BamH I tr-3 Sph I Apal Nde I hearts derived from both the TRE" muta and TRE-' muta mice were comparable to one another The transgene in these lines responded to thehypothyroid state in an aberrant manner in thata total shutdownof CAT activityin the ventricles. The hypothyroid ventricles from TRE-' muta and TRE-' mutacontinued to express low levels of CAT activity. N-5.5 implicates TREl and TREz in mediating the a-MHC ventricular expression by thyroxine
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