Analysis of sense and naturally occurring antisense transcripts of myosin heavy chain in the human myocardium

Luther, Hans Peter; Podlowski, Svenia; Hetzer, Roland; Baumann, Gert

doi:10.1002/1097-4644(20010315)80:4<596::aid-jcb1014>3.0.co;2-y

Cited by 16 publications

(9 citation statements)

References 29 publications

(39 reference statements)

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“…Furthermore, this report of the antisense expression has not linked its expression with a functional significance. More recently, Luther et al (33)(34)(35) reported the expression of antisense MHC mRNA in both the rat and human myocardium, and it was proposed that this antisense MHC regulates translation of the sense mRNA into protein. In these studies (33)(34)(35), there was no differentiation between primary transcript versus processed mature mRNA.…”

Section: Discussionmentioning

confidence: 99%

Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching

Haddad

Bodell

Qin

et al. 2003

Journal of Biological Chemistry

102

100

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A novel mechanism of regulation of cardiac ␣ and ␤ myosin heavy chain gene by naturally occurring antisense transcription was elucidated via pre-mRNA analysis. Herein, we report the expression of an antisense ␤ myosin heavy chain RNA in the normal rodent myocardium. The pattern of expression of the antisense ␤MHC RNA (␤ RNA) under altered thyroid state and in diabetes directly correlates with that of the ␣ pre-mRNA/mRNA, whereas it negatively correlates with the ␤ mRNA expression. Rapid amplification of the 5 end shows that this antisense transcript originates 2 kb downstream of the ␤ gene, and it is transcribed across the entire ␤ gene from the opposite strand. Our results demonstrate that the ␤-␣ myosin heavy chain intergenic DNA possesses a bidirectional transcriptional activity, one direction transcribing the ␣ gene, and the opposite direction transcribing the antisense ␤ RNA. This process turns on the ␣ expression, and it simultaneously turns off that of the ␤ and thus coordinates ␣ and ␤ expression in an opposite fashion. Comparative analyses of the intergenic DNA sequence across five mammalian species revealed a conserved region that is proposed to be a common regulatory region for the ␣ and antisense ␤ promoter. This finding unravels the mechanism of cardiac ␣-␤ gene switching and implicates the role of cardiac myosin gene organization with their function.Cardiac muscle expresses two myosin heavy chain (MHC) 1 isoforms designated as ␣ (high ATPase) and ␤ (low ATPase) that are encoded by two distinct genes located in close proximity on the same chromosome (1-4). The MHC is the molecular motor driving muscle contraction, and its phenotypic composition regulates the intrinsic contraction properties of the heart (5, 6). Cardiac MHC isoform expression is developmentally regulated (5), and it can change totally in either direction under certain pathophysiological states (7-9). For example during the first 3 weeks of postnatal life of rodents there is a complete switch from a predominant ␤MHC expression at birth (Ͼ90%) to a predominant ␣MHC expression at 3 weeks of age (Ͼ95%). Throughout adult life, the ␣MHC expression predominates in a normal rodent heart, with ␤MHC expression gradually increasing as the animal gets older. At any time during life, the pattern of MHC expression can be altered. Hypothyroidism and diabetes are associated with a switch in the cardiac MHC gene expression from a predominant ␣MHC to a predominant ␤MHC. In contrast, thyroid hormones treatment increases the ␣MHC expression while down-regulating the ␤MHC expression. The exact molecular mechanisms causing this tightly coordinated regulation of these two genes remains unclear. Thyroid hormone has been shown to be a major regulator of MHC gene expression, and its regulation is thought to occur mainly via transcriptional processes regulating each gene independently in a well coordinated fashion (8). Several thyroid responsive elements have been located on the promoter of the ␣MHC gene, whereas the localized action of thyroid hormone on the ...

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Section: Discussionmentioning

confidence: 99%

Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching

Haddad

Bodell

Qin

et al. 2003

Journal of Biological Chemistry

102

100

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“…Of note, there is an uncharacterized phylogenetically conserved transcript (BC039102) overlapping the 3' end of SEPP1 in an antisense orientation. Resequencing at the SEPP1 locus was expanded to include putative exons and the promoter region corresponding to this antisense transcript because of the possibility that overlapping transcripts might post-transcriptionally regulate each other's expression [67,68]. TXNRD1 exhibits alternative splicing at the 5' end.…”

Section: Methodsmentioning

confidence: 99%

Polymorphism analysis of six selenoprotein genes: support for a selective sweep at the glutathione peroxidase 1 locus (3p21) in Asian populations

et al. 2006

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Background: There are at least 25 human selenoproteins, each characterized by the incorporation of selenium into the primary sequence as the amino acid selenocysteine. Since many selenoproteins have antioxidant properties, it is plausible that inter-individual differences in selenoprotein expression or activity could influence risk for a range of complex diseases, such as cancer, infectious diseases as well as deleterious responses to oxidative stressors like cigarette smoke. To capture the common genetic variants for 6 important selenoprotein genes (GPX1, GPX2, GPX3, GPX4, TXNRD1, and SEPP1) known to contribute to antioxidant host defenses, a resequence analysis was conducted across these genes with particular interest directed at the coding regions, intron-exon borders and flanking untranslated regions (UTR) for each gene in an 102 individual population representative of 4 major ethnic groups found within the United States.

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“…To detect cTnI-specific RNAs, we performed a Northern blot as described previously (Luther et al 2001). Up to 1.5 µg of isolated rat poly(A) + RNA was heat denatured for 5 min at 65°C and subsequently loaded on a 1% agarose gel (1× MOPS, 2% formaldehyde).…”

Section: Gel Electrophoresis and Blotting Of Rnamentioning

confidence: 99%

Detection of a novel sense–antisense RNA-hybrid structure by RACE experiments on endogenous troponin I antisense RNA

Bartsch

Voigtsberger²,

Baumann³

et al. 2004

RNA

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Conformational changes in the troponin/tropomyosin complex significantly alter the mechanical properties of cardiac muscle. Phosphorylation of cardiac troponin I, part of the troponin/tropomyosin complex, reduces calcium affinity, which leads to increased relaxation of cardiac muscle. Because cardiac troponin I plays a central role in tuning the heart to different work demands, detailed knowledge of troponin I protein regulation is required. Our group previously detected naturally occurring antisense RNA for troponin I in human and rat hearts, and here, attempt to unravel the structure of rat cardiac troponin I antisense RNA. We performed rapid amplification of cDNA ends (RACE) experiments and discovered antisense sequences identical to a copy of the sense mRNA, which led us to conclude that the antisense RNA must be transcribed from troponin I mRNA in the cytoplasm. Moreover, we isolated RNA structures comprising sense and antisense sequences in one continuous molecule. As we found no homolog structures described in the literature, we called this "hybrid RNA." Because a duplex formation was demonstrated previously we concluded that hybrid RNA is a consequence of a tight interaction between sense and antisense troponin I RNA in vivo, which we discuss in the article.

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Analysis of sense and naturally occurring antisense transcripts of myosin heavy chain in the human myocardium

Cited by 16 publications

References 29 publications

Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching

Role of Antisense RNA in Coordinating Cardiac Myosin Heavy Chain Gene Switching

Polymorphism analysis of six selenoprotein genes: support for a selective sweep at the glutathione peroxidase 1 locus (3p21) in Asian populations

Detection of a novel sense–antisense RNA-hybrid structure by RACE experiments on endogenous troponin I antisense RNA

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