scholarly journals Regulation of alternative splicing of Gtf2ird1 and its impact on slow muscle promoter activity

2003 ◽  
Vol 374 (2) ◽  
pp. 359-367 ◽  
Author(s):  
Enoch S. E. TAY ◽  
Kim L. GUVEN ◽  
Nanthakumar SUBRAMANIAM ◽  
Patsie POLLY ◽  
Laura L. ISSA ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Alternative Splicing ◽  
Troponin I ◽  
Cytogenet Cell ◽  
Gene Encoding ◽  
Slow Fibre ◽  
Reverse Transcription Pcr ◽  
Multiple Promoters ◽  
Abnormal Gait ◽  
Muscle Gene

A human MusTRD [muscle TFII-I repeat domain (RD)-containing protein] isoform was originally identified in a yeast one-hybrid screen as a protein that binds the slow fibre-specific enhancer of the muscle gene troponin I slow [O'Mahoney, Guven, Lin, Joya, Robinson, Wade and Hardeman (1998) Mol. Cell. Biol. 18, 6641–6652]. MusTRD shares homology with the general transcription factor TFII-I by the presence of diagnostic I-RDs [Roy (2001) Gene 274, 1–13]. The human gene encoding MusTRD, GTF2IRD1 (WBSCR11/GTF3), was subsequently located on chromosome 7q11.23, a region deleted in the neurodegenerative disease, Williams–Beuren Syndrome [Osborne, Campbell, Daradich, Scherer, Tsui, Franke, Peoples, Francke, Voit, Kramer et al. (1999) Genomics 57, 279–284; Franke, Peoples and Francke (1999) Cytogenet. Cell. Genet. 86, 296–304; Tassabehji, Carette, Wilmot, Donnai, Read and Metcalfe (1999) Eur. J. Hum. Genet. 7, 737–747]. The haploinsufficiency of MusTRD has been implicated in the myopathic aspect of this disease, which manifests itself in symptoms such as lowered resistance to fatigue, kyphoscoliosis, an abnormal gait and joint contractures [Tassabehji, Carette, Wilmot, Donnai, Read and Metcalfe (1999) Eur. J. Hum. Genet. 7, 737–747]. Here, we report the identification of 11 isoforms of MusTRD in mouse skeletal muscles. These isoforms were isolated from a mouse skeletal muscle cDNA library and reverse transcription–PCR on RNA from various adult and embryonic muscles. The variability in these isoforms arises from alternative splicing of a combination of four cassettes and two mutually exclusive exons, all in the 3′ region of the primary transcript of Gtf2ird1, the homologous mouse gene. The expression of some of these isoforms is differentially regulated spatially, suggesting individual regulation of the expression of these isoforms. Co-transfection studies in C2C12 muscle cell cultures reveal that isoforms differentially regulate muscle fibre-type-specific promoters. This indicates that the presence of different domains of MusTRD influences the activity exerted by this molecule on multiple promoters active in skeletal muscle.

Complex fiber-type-specific expression of fast skeletal muscle troponin I gene constructs in transgenic mice

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 691-701
Author(s):  
P.L. Hallauer ◽  
H.L. Bradshaw ◽  
K.E. Hastings
Keyword(s):  
Skeletal Muscle ◽  
Differential Expression ◽  
Expression Pattern ◽  
Troponin I ◽  
Fiber Type ◽  
Fiber Types ◽  
Fast Skeletal Muscle ◽  
Fast Fiber ◽  
Muscle Gene ◽  
High Level

We analyzed, in transgenic mice, the cellular expression pattern of the quail fast skeletal muscle troponin I (TnIfast) gene and of a chimeric reporter construct in which quail TnIfast DNA sequences drive expression of E. coli beta-galactosidase (beta-gal). Both constructs were actively expressed in skeletal muscle and specifically in fast, as opposed to slow, muscle fibers. Unexpectedly, both constructs showed a marked differential expression among the adult fast fiber subtypes according to the pattern IIB > IIX > IIA. This expression pattern was consistent in multiple lines and differed from the endogenous mouse TnIfast pattern, which shows approximately equal expression in all fast fibers. These observations indicate that distinct regulatory mechanisms contribute to high-level expression of TnIfast in the various fast fiber subtypes and suggest that the outwardly simple pattern of equal expression in all fast fiber types shown by the endogenous mouse TnIfast gene is based on an intricate system of counterbalancing mechanisms. The adult expression pattern of the TnIfast/beta-gal construct emerged in a two-stage developmental process. Differential expression in fast versus slow fibers was evident in neonatal animals, although expression in fast fibers was relatively weak and homogeneous. During the first two weeks of postnatal life, expression in maturing IIB fibers was greatly increased whereas that in IIA/IIX fibers remained weak, giving rise to marked differential expression among fast fiber types. Thus at least two serially acting (pre- and post-natal) fiber-type-specific regulatory mechanisms contribute to high-level gene expression in adult fast muscle fibers. Unexpected similarities between TnIfast transgene expression and that of the myosin heavy chain gene family (which includes differentially expressed IIB-, IIX- and IIA-specific members) suggest that similar mechanisms may regulate adult fast muscle gene expression in a variety of unrelated muscle gene families.

Skeletal muscle gene transfer: regeneration-associated deregulation of fast troponin I fiber type specificity

2000 ◽  
Vol 278 (6) ◽  
pp. C1266-C1274 ◽  
Author(s):  
Patricia L. Hallauer ◽  
George Karpati ◽  
Kenneth E. M. Hastings
Keyword(s):  
Skeletal Muscle ◽  
Gene Transfer ◽  
Plasmid Dna ◽  
Troponin I ◽  
Recombinant Adenovirus ◽  
Fiber Type ◽  
Direct Gene Transfer ◽  
Adult Muscle ◽  
Direct Gene ◽  
Muscle Gene

Direct gene transfer into skeletal muscle in vivo presents a convenient experimental approach for studies of adult muscle gene regulatory mechanisms, including fast vs. slow fiber type specificity. Previous studies have reported preferential expression of fast myosin heavy chain and slow myosin light chain and troponin I (TnIslow) gene constructs in muscles enriched in the appropriate fiber type. We now report a troponin I fast (TnIfast) direct gene transfer study. We injected into the mouse soleus muscle plasmid DNA or recombinant adenovirus carrying a TnIfast/ β-galactosidase (β-gal) reporter construct that had previously been shown to be expressed specifically in fast fibers in transgenic mice. Surprisingly, microscopic histochemical analysis 1 and 4 wk postinjection showed similar TnIfast/β-gal expression in fast and slow fibers. A low but significant level of muscle fiber segmental regeneration was evident in muscles 1 wk postinjection, and TnIfast/β-gal expression was preferentially targeted to regenerating fiber segments. This finding can explain why TnIfast constructs are deregulated with regard to fiber type specificity, whereas the myosin constructs previously studied are not. The involvement of regenerating fiber segments in transduction by plasmid DNA and recombinant adenoviruses injected into intact normal adult muscle is an unanticipated factor that should be taken into account in the planning and interpretation of direct gene transfer experiments.

scholarly journals HIRA stabilizes skeletal muscle lineage identity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joana Esteves de Lima ◽  
Reem Bou Akar ◽  
Léo Machado ◽  
Yuefeng Li ◽  
Bernadette Drayton-Libotte ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Lineage ◽  
Promoter Regions ◽  
Cell Fates ◽  
Regulatory Regions ◽  
Muscle Stem Cells ◽  
Adult Mice ◽  
H3k4me3 Mark ◽  
Muscle Genes ◽  
Muscle Gene

AbstractThe epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

scholarly journals The phosphorylation of troponin I from cardiac muscle

1975 ◽  
Vol 149 (3) ◽  
pp. 525-533 ◽  
Author(s):  
H A Cole ◽  
S V Perry
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Cyclic Amp ◽  
Cardiac Muscle ◽  
Cardiac Troponin ◽  
Troponin I ◽  
Cardiac Troponin I ◽  
Phosphorylase Kinase ◽  
Dependent Protein Kinase ◽  
Dependent Protein

1. Troponin I isolated from fresh cardiac muscle by affinity chromatography contains about 1.9 mol of covalently bound phosphate/mol. Similar preparations of white-skeletal-muscle troponin I contain about 0.5 mol of phosphate/mol. 2. A 3':5'-cyclic AMP-dependent protein kinase and a protein phosphatase are associated with troponin isolated from cardiac muscle. 3. Bovine cardiac 3':5'-cyclic AMP-dependent protein kinase catalyses the phosphorylation of cardiac troponin I 30 times faster than white-skeletal-muscle troponin I. 4. Troponin I is the only component of cardiac troponin phosphorylated at a significant rate by the endogenous or a bovine cardiac 3':5'-cyclic AMP-dependent protein kinase. 5. Phosphorylase kinase catalyses the phosphorylation of cardiac troponin I at similar or slightly faster rates than white-skeletal-muscle troponin I. 6. Troponin C inhibits the phosphorylation of cardiac and skeletal troponin I catalysed by phosphorylase kinase and the phosphorylation of white skeletal troponin I catalysed by 3':5'-cyclic AMP-dependent protein kinase; the phosphorylation of cardiac troponin I catalysed by the latter enzyme is not inhibited.

scholarly journals Fast skeletal muscle-specific expression of a quail troponin I gene in transgenic mice.

1988 ◽  
Vol 8 (12) ◽  
pp. 5072-5079 ◽  
Author(s):  
P L Hallauer ◽  
K E Hastings ◽  
A C Peterson
Keyword(s):  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Troponin I ◽  
Fiber Type ◽  
Regulatory Elements ◽  
Evolutionary Divergence ◽  
Mrna Levels ◽  
Fast Skeletal Muscle ◽  
Specific Expression ◽  
Exon 2

We have produced seven lines of transgenic mice carrying the quail gene encoding the fast skeletal muscle-specific isoform of troponin I (TnIf). The quail DNA included the entire TnIf gene, 530 base pairs of 5'-flanking DNA, and 1.5 kilobase pairs of 3'-flanking DNA. In all seven transgenic lines, normally initiated and processed quail TnIf mRNA was expressed in skeletal muscle, where it accumulated to levels comparable to that in quail muscle. Moreover, in the three lines tested, quail TnIf mRNA levels were manyfold higher in a fast skeletal muscle (gastrocnemius) than in a slow skeletal muscle (soleus). We conclude that the cellular mechanisms directing muscle fiber type-specific TnIf gene expression are mediated by cis-regulatory elements present on the introduced quail DNA fragment and that they control TnIf expression by affecting the accumulation of TnIf mRNA. These elements have been functionally conserved since the evolutionary divergence of birds and mammals, despite the major physiological and morphological differences existing between avian (tonic) and mammalian (twitch) slow muscles. In lines of transgenic mice carrying multiple tandemly repeated copies of the transgene, an aberrant quail TnIf transcript (differing from normal TnIf mRNA upstream of exon 2) also accumulated in certain tissues, particularly lung, brain, spleen, and heart tissues. However, this aberrant transcript was not detected in a transgenic line which carries only a single copy of the quail gene.

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