A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit.

Lazar, Mitchell A.; Hodin, Richard A.; Darling, Douglas S.; Chin, William W.

doi:10.1128/mcb.9.3.1128

Cited by 308 publications

(177 citation statements)

References 42 publications

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“…In adult mice, rev-erbA␣ mRNA is an ubiquitously expressed transcript, and the most abundant levels have been observed in brown fat, skeletal muscle, and brain (6,11,27). In the adult homozygous and heterozygous rev-erbA␣ mutant mice, fast-and slow-twitch skeletal muscles showed a normal distribution of muscle fiber types and mitochondrial enzyme activities.…”

Section: Discussionmentioning

confidence: 99%

“…rev-erbA␣ and TR␣ 2 mRNAs are complementary for a stretch of 269 nucleotides because of bidirectional transcription of a partially common exon. The peculiar arrangement of the rev-erbA␣ gene has led to the suggestion that its transcription could interfere with the expression of the thyroid hormone receptor (21,27) by regulating alternative processing of ␣ 1 and ␣ 2 mRNAs in vitro by an antisense mechanism (36). Thus relatively modest changes in splice site selection could cause major changes in cellular T 3 responsiveness (27).…”

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“…The peculiar arrangement of the rev-erbA␣ gene has led to the suggestion that its transcription could interfere with the expression of the thyroid hormone receptor (21,27) by regulating alternative processing of ␣ 1 and ␣ 2 mRNAs in vitro by an antisense mechanism (36). Thus relatively modest changes in splice site selection could cause major changes in cellular T 3 responsiveness (27). Other orphan receptors, e.g., COUPTF II, RVR, ROR␣, and ROR␥, are abundantly expressed in skeletal muscle (11,22).…”

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Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

Pircher¹,

Chomez²,

Yu³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Aberrant expression of myosin isoforms in skeletal muscles from mice lacking the rev-erbA␣ orphan receptor gene. Am J Physiol Regul Integr Comp Physiol 288: R482-R490, 2005. First published September 16, 2004; doi:10.1152/ajpregu.00690.2003.-The rev-erbA␣ orphan protein belongs to the steroid nuclear receptor superfamily. No ligand has been identified for this protein, and little is known of its function in development or physiology. In this study, we focus on 1) the distribution of the rev-erbA␣ protein in adult fast-and slow-twitch skeletal muscles and muscle fibers and 2) how the rev-erbA␣ protein influences myosin heavy chain (MyHC) isoform expression in mice heterozygous (ϩ/Ϫ) and homozygous (Ϫ/Ϫ) for a rev-erbA␣ protein null allele. In the fast-twitch extensor digitorum longus muscle, rev-erbA␣ protein expression was linked to muscle fiber type; however, MyHC isoform expression did not differ between wild-type, ϩ/Ϫ, or Ϫ/Ϫ mice. In the slow-twitch soleus muscle, the link between rev-erbA␣ protein and MyHC isoform expression was more complex than in the extensor digitorum longus. Here, a significantly higher relative amount of the ␤/slow (type I) MyHC isoform was observed in both rev-erbA␣ Ϫ/Ϫ and ϩ/Ϫ mice vs. that shown in wild-type controls. A role for the ratio of thyroid hormone receptor proteins ␣ 1 to ␣2 in modulating MyHC isoform expression can be ruled out because no differences were seen in MyHC isoform expression between thyroid hormone receptor ␣ 2-deficient mice (heterozygous and homozygous) and wild-type mice. Therefore, our data are compatible with the rev-erbA␣ protein playing an important role in the regulation of skeletal muscle MyHC isoform expression. orphan nuclear receptors; thyroid hormone; fast-and slow-twitch muscle THE VARIABLE EXPRESSION OF myofibrillar protein isoforms is a major determinant of the contractile properties and ATPase activities of skeletal and myocardial fibers (3, 50). The myosin heavy chain (MyHC) molecule is the most abundant myofibrillar protein and is encoded by a multigene family consisting of several members (35). Several isoforms have now been described in rodent skeletal muscles, including one slow isoform (type I or ␤/slow), three fast (IIa, IIx/d, and IIb), and two developmental (embryonic and neonatal/perinatal/fetal) isoforms, which are all coded by distinct genes (50). Four other MyHC isoforms, slow tonic, superfast IIm, ␣-cardiac-like, and extraocular myosin, are expressed in a few specialized muscles (7, 50). Despite their similarity in primary structure, the expression of different MyHC isoforms is precisely regulated in a tissue-specific and developmental stage-specific manner (50, 52). In addition, innervation patterns (33, 45, 46), altered physiological stimuli (34, 46), and various hormones (19) are known to have a significant impact on MyHC isoform expression.Skeletal muscle is a major target for hormone action. Thyroid hormone is one of the most potent regulators of skeletal muscle MyHC isoform expression in mammals, and it has been suggested...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

Pircher¹,

Chomez²,

Yu³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, the gene sequence for Rev-erbA␣, the TR-related protein encoded by the opposite strand of TR␣ (18,19), remains intact. In contrast to the TR␣ Ϫ/Ϫ mice, the TR␣ o/o mice survive without rescue by TH treatment.…”

Section: Experimental Methods Animal Proceduresmentioning

confidence: 99%

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha

Macchia¹

2000

Proceedings of the National Academy of Sciences

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Only three of the four thyroid hormone receptor (TR) isoforms, ␣1, ␤1, and ␤2, bind thyroid hormone (TH) and are considered to be true TRs. TR␣2 binds to TH response elements on DNA, but its role in vivo is still unknown. We produced mice completely deficient in TR␣ (TR␣ o/o ) that maintain normal serum thyroid-stimulating hormone (TSH) concentration despite low serum thyroxine (T4), suggesting increased sensitivity to TH. We therefore examined the effects of TH (L-3,3 ,5-triiodothyronine, L-T3) given to TH-deprived and to intact TR␣ o/o mice. Controls were wild-type (WT) mice of the same strain and mice resistant to TH due to deficiency in TR␤ (TR␤ ؊/؊ ). In liver, T3 produced significantly greater responses in TR␣ o/o and smaller responses in TR␤ ؊/؊ as compared with WT mice. In contrast, cardiac responses to L-T3 were absent or reduced in TR␣ o/o , whereas they were similar in WT and TR␤ ؊/؊ mice, supporting the notion that TR␣1 is the dominant TH-dependent TR isoform in heart. 5-Triiodothyronine (L-T3) given to intact mice produced a greater suppression of serum T4 in TR␣ o/o than it did in WT mice and reduced by a greater amount the TSH response to TSH-releasing hormone. This is an in vivo demonstration that a TR deficiency can enhance sensitivity to TH. This effect is likely due to the abrogation of the constitutive ''silencing'' effect of TR␣2 in tissues expressing the TR␤ isoforms.T hyroid hormone (TH) action is mediated through specific nuclear TH receptors (TRs) functioning as ligand-dependent transcription factors that increase or decrease the expression of target genes (1-3). There are two TR genes. The TR␤ locus generates the ␤1 and ␤2 receptors by using two different promoters and alternative splicing. The TR␣ locus encodes TR␣1, a molecule containing 410 aa, and three proteins that do not bind the ligand, triiodothyronine (T 3 ) (4-7) (GenBank accession no. AI322342). TR␣2, which results from an alternative splicing of the TR␣ primary transcript, has 492 aa, the first 370 of which are identical to TR␣1. TR⌬␣1 and TR⌬␣2, molecules of approximately 154 and 237 aa, respectively, are generated from an internal promoter located in intron 7 of the TR␣ locus (6). The function of TR␣2, which has a wide tissue distribution (8), and that of TR⌬␣1 and TR⌬␣2, found mainly in brain, gut, and lung (6), are still unknown. However, all have been shown to inhibit ligand-dependent transactivation of TR␤ and TR␣1, a phenomenon termed the dominant negative effect (6, 9-11, ** ).The relative contribution of the two TR gene products in mediating TH responses is poorly understood because of the paucity of information regarding in vivo function. In vitro DNA binding studies and functional assays in transfected cells have generated conflicting results concerning the specific effect of TR isoforms in gene regulation (12, 13). Interpretation is complicated, however, because data are derived from artificial systems using the overexpression of chimeric gene constructs that may not be faithful models of events occurring in the...

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“…Until recently, it was believed that they occur much less frequently in eukaryotic nuclear genomes. Although their presence in human and other species' genomes was reported previously (Williams and Fried 1986;Lazar et al 1989;Miyajima et al 1989;Burke et al 1998;Cooper et al 1998;Bachman et al 1999;Shintani et al 1999;Misener and Walker 2000;Morelli et al 2000;Slavov et al 2000;Zhuo et al 2001), until lately very little was known about their frequency and genome-wide distribution. Recent reports show that overlapping genes occur relatively frequently in human and other mammalian genomes (Kiyosawa and Abe 2002;Lehner et al 2002;Okazaki et al 2002;Shendure and Church 2002;Yelin et al 2003).…”

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Mammalian Overlapping Genes: The Comparative Perspective

Veeramachaneni¹,

Makałowski²,

Galdzicki³

et al. 2004

Genome Res.

128

130

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It is believed that 3.2 billion bp of the human genome harbor ∼35,000 protein-coding genes. On average, one could expect one gene per 300,000 nucleotides (nt). Although the distribution of the genes in the human genome is not random,it is rather surprising that a large number of genes overlap in the mammalian genomes. Thousands of overlapping genes were recently identified in the human and mouse genomes. However,the origin and evolution of overlapping genes are still unknown. We identified 1316 pairs of overlapping genes in humans and mice and studied their evolutionary patterns. It appears that these genes do not demonstrate greater than usual conservation. Studies of the gene structure and overlap pattern showed that only a small fraction of analyzed genes preserved exactly the same pattern in both organisms

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A novel member of the thyroid/steroid hormone receptor family is encoded by the opposite strand of the rat c-erbA alpha transcriptional unit.

Cited by 308 publications

References 42 publications

Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

Aberrant expression of myosin isoforms in skeletal muscles from mice lacking therev-erbAαorphan receptor gene

Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor alpha

Mammalian Overlapping Genes: The Comparative Perspective

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