Regulation of gene expression by natural antisense RNA transcripts

Knee, Rai; Murphy, Paul R.

doi:10.1016/s0197-0186(96)00108-8

Cited by 109 publications

(56 citation statements)

References 109 publications

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“…This phenomenon was initially thought not to occur in eukaryotes, but has recently been demonstrated in a number of genes (Knee & Murphy 1997). Antisense transcription has been implicated in regulating eukaryotic gene expression by inhibiting N-myc RNA elongation (Krystal et al 1988), RNA editing for the glutamate receptor (Higuchi et al 1993), mRNA splicing for the thyroid hormone receptor (Munroe & Lazar 1991), mRNA transport in the myelin deficient mouse gene (Tosic et al 1990), mRNA half life for basic fibroblast growth factor (Kinelman & Kirschner 1987), and mRNA translation for the myosin heavy chain (Heywood 1986).…”

Section: Significance Of the Antisense Transcriptmentioning

confidence: 99%

“…Interestingly, the open reading frame antisense transcript of the GnRH gene is expressed in the heart (Adelman et al 1987) but a translated protein has not been described. It has been suggested that the localization of GnRH antisense RNA in the nucleus may indicate a role in GnRH mRNA processing (Knee & Murphy 1997).…”

Section: Significance Of the Antisense Transcriptmentioning

confidence: 99%

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A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

Millar

Conklin²,

Lofton–Day³

et al. 1999

Journal of Endocrinology

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Gonadotropin releasing hormone (GnRH) regulates the reproductive system through a specific G-protein-coupled receptor (GPCR) in pituitary gonadotropes. The existence of two (or more) forms of GnRH in most vertebrates suggested the existence of GnRH receptor subtypes (I and II). Using sequence information for extracellular loop 3 of a putative Type II GnRH receptor from a reptile species, we have looked for a Type II GnRH receptor gene in the human genome EST (expressed sequence tag) database. A homolog was identified which has 45% and 41% amino acid identity with exons 2 and 3 of the known human GnRH pituitary receptor (designated Type I) and much lower homology with all other GPCRs. A total of 27 contiguous ESTs was found and comprised a continuous sequence of 1642 nucleotides. The EST sequences were confirmed in the cloned human gene and in PCR products of cDNA from several tissues. All EST transcripts detected were in the antisense orientation with respect to the novel GnRH receptor sequence and were highly expressed in a wide range of human brain and peripheral tissues. PCR of cDNA from a wide range of tissues revealed that intronic sequence equivalent to intron 2 of the Type I GnRH receptor was retained. The failure to splice out putative intron sequences in transcripts which spanned exon-intron boundaries is expected in antisense transcripts, as candidate donor and acceptor sites were only present in the gene when transcribed in the orientation encoding the GnRH receptor homolog. No transcripts extended 5 to the sequence corresponding to intron 2 of the Type I GnRH as the antisense transcripts terminated in poly A due to the presence of a polyadenylation signal sequence in the putative intron 2 when transcribed in the antisense orientation. These findings suggest that a Type II GnRH receptor gene has arisen during vertebrate evolution and is also present in the human. However, the receptor may have become vestigial in the human, possibly due to the abundant and universal tissue transcription of the opposite DNA strand to produce antisense RNA.

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Section: Significance Of the Antisense Transcriptmentioning

confidence: 99%

Section: Significance Of the Antisense Transcriptmentioning

confidence: 99%

A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

Millar

Conklin²,

Lofton–Day³

et al. 1999

Journal of Endocrinology

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“…NATs have been identified recently as being involved in the regulation of gene expression in eukaryotes (15,16), and NATs have been identified in the human genome (17)(18)(19). Their involvement in gene regulation is quite variable, and no generalized mechanism exists, but examples include transcription interference (20,21), RNA editing (22), and inhibition of splicing (23).…”

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confidence: 99%

Dynamics of Myosin Heavy Chain Gene Regulation in Slow Skeletal Muscle

Pandorf

Haddad

Roy

et al. 2006

Journal of Biological Chemistry

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The evolutionarily conserved order of the skeletal muscle myosin heavy chain (MHC) genes and their close tandem proximity on the same chromosome are intriguing and may be important for their coordinated regulation. We investigated type II MHC gene regulation in slow-type muscle fibers undergoing a slow to fast MHC transformation in response to inactivity, 7 days after spinal cord isolation (SI) in rats. We examined the transcriptional products of both the sense and antisense strands across the IIa-IIx-IIb MHC gene locus. A strand-specific reverse transcription (RT)-PCR approach was utilized to study the expression of the mRNA, the primary transcript (pre-mRNA), the antisense RNA overlapping the MHC genes, and both the intergenic sense and antisense RNAs. Results showed that the mRNA and pre-mRNA of each MHC had a similar response to SI, suggesting regulation of these genes at the transcriptional level. In addition, we detected previously unknown antisense strand transcription that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs (antisense products of the IIa, IIx, and IIb genes, respectively). The aII NAT begins in the IIa-IIx intergenic region in close proximity to the IIx promoter, extends across the 27-kb IIa MHC gene, and continues to the IIa MHC gene promoter. The expression of the aII NAT was significantly up-regulated in muscles after SI, was negatively correlated with IIa MHC gene expression, and was positively correlated with IIx MHC gene expression. The exact role of the aII NAT is not clear; however, it is consistent with the inhibition of IIa MHC gene transcription. In conclusion, NATs may mediate cross-talk between adjacent genes, which may be essential to the coordinated regulation of the skeletal muscle MHC genes during dynamic phenotype shifts.Skeletal muscle is highly adaptable when subjected to altered loading and hormone states. Its size, metabolic makeup, and contractile properties can all be altered to optimize function (1). Variability in contractile properties is achieved mainly by diversification in the motor protein myosin heavy chain (MHC), 2 where different isoforms are encoded by distinct genes (1, 2). Of this family of eight MHC genes, six are tandemly linked and span ϳ420 kb in the rat on chromosome 10, with embryonic MHC situated at the most 5Ј end, sequentially followed by IIa, IIx, IIb, neonatal, and extraocular MHC. ␤ (or type I) and ␣ MHCs are located tandemly on separate chromosomes (chromosome 14 in the rat); they span ϳ50 kb and are separated by 4.5 kb. Interestingly, the genomic order and orientation on the chromosomes of the MHC genes are conserved in all mammalian species, leading researchers to suspect that this organization might be an important feature in the strategy for the coordinated regulation of these genes (2-5).Types I, IIa, IIx, and IIb, in respective order of increasing ATPase activity, are the four predominately exp...

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“…Only few examples have been characterized in experimental detail and the physiological relevance of the large-scale antisense transcription is speculative. [16][17][18][19][20][21][22][23] The widespread occurrence and the apparent poor cross species conservation of bi-directional transcription prompted the rather nihilistic suggestion of "transcriptional noise". 24 Such noise it is argued would only be a problem if a cellular system lacked the tools to deal with the "pollution"-and, with RNAi and RNA editing such mechanisms seem to be in place.…”

Section: Natural Antisense Transcripts In Focusmentioning

confidence: 99%

Natural Antisense Transcripts

Werner

2005

RNA Biology

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The sequencing of whole genomes and the subsequent annotation of cDNAs revealed that about 20% of human and mouse genes overlap resulting in potential pairs of sense and antisense transcripts. An increasing number of experimentally identified antisense transcripts concur with this predication.Characterization of overlapping transcripts in various species indicates that this form of RNA-mediated gene regulation represents a widespread phenomenon. However, the physiological relevance of natural antisense transcripts remains obscure. Genomic studies suggest that duplex formation between sense and antisense is required for biological function.Antisense transcripts play an established role in imprinting and X-chromosome inactivation and genomic rearrangements as observed in B and T leukocytes. Only a relatively small percentage of the predicted antisense transcripts are related to these biological phenomena that are also related to mono-allelic expression.Consequently, there are at least two categories of natural antisense transcripts that show significant differences with regard to their biological function as well as the potential mechanisms involved.

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Regulation of gene expression by natural antisense RNA transcripts

Cited by 109 publications

References 109 publications

A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

Dynamics of Myosin Heavy Chain Gene Regulation in Slow Skeletal Muscle

Natural Antisense Transcripts

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