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Gordon G Carmichael

Publications and source records attributed to Gordon G Carmichael.

12 recordsLinked to original sources
PubMed2006

Evidence for variation in abundance of antisense transcripts between multicellular animals but no relationship between antisense transcriptionand organismic complexity.

Given that humans have about the same number of genes as mice and not so many more than worm, what makes us more complex? Antisense transcripts are implicated in many aspects of gene regulation. Is there a functional connection between antisense transcription and organismic complexity, that is, is antisense regulation especially prevalent in humans? We used the same robust protocol to identify antisense transcripts in humans and five other metazoan genomes (mouse, rat, chicken, fruit fly, and nematode), and found that the estimated proportions of genes involved in antisense transcription are highly sensitive to the number of transcripts included in the analysis. By controlling for transcript abundance, we find that the probability that any given transcript is putatively involved in sense-antisense regulation is no higher in humans than in other vertebrates but appears unusually high in flies and especially low in nematodes. Similarly, there is no evidence that the proportion of sense-antisense transcripts is especially higher in humans than other vertebrates in a given subset of transcript sequences such as mRNAs, coding sequences, conserved, or nonconserved transcripts. Although antisense transcription might be enriched in mammalian brains compared with nonbrain tissues, it is no more enriched in human brain than in mouse brain. Overall, therefore, while we see striking variation between multicellular animals in the abundance of antisense transcripts, there is no evidence for a link between antisense transcription and organismic complexity. More particularly, we see no evidence that humans are in any way unusual among the vertebrates in this regard. Instead, our results suggest that antisense transcription might be prevalent in almost all metazoan genomes, nematodes being an unexplained exception.

Animals↗
PubMed2005

Evidence for a preferential targeting of 3'-UTRs by cis-encoded natural antisense transcripts.

Although both the 5'- and 3'-untranslated regions (5'- and 3'-UTRs) of eukaryotic mRNAs may play a crucial role in posttranscriptional gene regulation, we observe that cis-encoded natural antisense RNAs have a striking preferential complementarity to the 3'-UTRs of their target genes in mammalian (human and mouse) genomes. A null neutral model, evoking differences in the rate of 3'-UTR and 5'-UTR extension, could potentially explain high rates of 3'-to-3' overlap compared with 5'-to-5' overlap. However, employing a simulation model we show that this null model probably cannot explain the finding that 3'-to-3' overlapping pairs have a much higher probability (>5 times) of conservation in both mouse and human genomes with the same overlapping pattern than do 5'-to-5' overlaps. Furthermore, it certainly cannot explain the finding that overlapping pairs seen in both genomes have a significantly higher probability of having co-expression and inverse expression (i.e. characteristic of sense-antisense regulation) than do overlapping pairs seen in only one of the two species. We infer that the function of many 3'-to-3' overlaps is indeed antisense regulation. These findings underscore the preference for, and conservation of, 3'-UTR-targeted antisense regulation, and the importance of 3'-UTRs in gene regulation.

3' Untranslated Regions↗
PubMed2005

SINEs point to abundant editing in the human genome.

Recent bioinformatic analyses suggest that almost all human transcripts are edited by adenosine deaminases (ADARs), converting adenosines to inosines. Most of this editing is in Alu element transcripts, which are unique to primates. This editing might have no function or might be involved in functions such as the regulation of splicing, chromatin or nuclear localization of transcripts.

Adenosine Deaminase↗
PubMed2005

Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin.

The fate of double-stranded RNA (dsRNA) in the cell depends on both its length and location . The expression of dsRNA in the nucleus leads to several distinct consequences. First, the promiscuous deamination of adenosines to inosines by dsRNA-specific adenosine deaminase (ADAR) can lead to the nuclear retention of edited transcripts . Second, dsRNAs might induce heterochromatic gene silencing through an RNAi-related mechanism . Is RNA editing also connected to heterochromatin? We report that members of the conserved Vigilin class of proteins have a high affinity for inosine-containing RNAs. In agreement with other work , we find that these proteins localize to heterochromatin and that mutation or depletion of the Drosophila Vigilin, DDP1, leads to altered nuclear morphology and defects in heterochromatin and chromosome segregation. Furthermore, nuclear Vigilin is found in complexes containing not only the editing enzyme ADAR1 but also RNA helicase A and Ku86/70. In the presence of RNA, the Vigilin complex recruits the DNA-PKcs enzyme, which appears to phosphorylate a discrete set of targets, some or all of which are known to participate in chromatin silencing. These results are consistent with a mechanistic link between components of the DNA-repair machinery and RNA-mediated gene silencing.

Animals↗
PubMed2005

Retention and repression: fates of hyperedited RNAs in the nucleus.

Double-stranded RNA (dsRNA) is often formed in the nuclei of mammalian cells, but in this compartment it does not induce the effects characteristic of cytoplasmic dsRNA. Rather, recent work has suggested that nuclear dsRNA is a target for the ADAR class of enzymes, which deaminate adenosines to inosines. Further, there are a number of distinct fates of such edited RNA, including nuclear retention and perhaps also gene silencing.

Active Transport, Cell Nucleus↗
PubMed2005

Human antisense genes have unusually short introns: evidence for selection for rapid transcription.

We suggest that small introns are favored in genes requiring a minimal response time ('nimble' genes), and that antisense genes might be prime candidates for such nimble genes. In this article, we show that antisense genes have significantly shorter introns than all other gene categories, which supports our proposal that the short introns of antisense genes might be functionally important and integrally related to their potential role in efficient gene regulation.

DNA, Antisense↗
PubMed2005

Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense-antisense transcripts.

Is sense-antisense (SA) pairing of transcripts a common mode of gene regulation in the human genome? Although >20% of human genes might form SA pairs, the extent to which they are involved in antisense regulation is unknown. Simultaneous expression of paired sense and antisense genes is an essential step and an important indicator of antisense regulation. In this article, we demonstrate that human SA pairs tend to be co-expressed and/or inversely expressed more frequently than expected by chance. Moreover, co-expressed and inversely expressed SA pairs exhibit a striking pattern of evolutionary conservation. These findings suggest that antisense regulation is a common and important mechanism of gene regulation in the human genome.

Animals↗
PubMed2004

Effects of length and location on the cellular response to double-stranded RNA.

Since double-stranded RNA (dsRNA) has not until recently generally been thought to be deliberately expressed in cells, it has commonly been assumed that the major source of cellular dsRNA is viral infections. In this view, the cellular responses to dsRNA would be natural and perhaps ancient antiviral responses. While the cell may certainly react to some dsRNAs as an antiviral response, this does not represent the only response or even, perhaps, the major one. A number of recent observations have pointed to the possibility that dsRNA molecules are not seen only as evidence of viral infection or recognized for degradation because they cannot be translated. In some instances they may also play important roles in normal cell growth and function. The purpose of this review is to outline our current understanding of the fate of dsRNA in cells, with a focus on the apparent fact that their fates and functions appear to depend critically not only on where in the cell dsRNA molecules are found, but also on how long they are and perhaps on how abundant they are.

Animals↗
PubMed2004

Methods for the analysis of adenosine-to-inosine editing in RNA.

In this work we describe methods for the analysis of RNAs that have been edited by the double-strand RNA-specific adenosine deaminase, ADAR. These RNAs contain inosine residues that can be detected and quantified by a variety of approaches, including base hydrolysis and thin-layer chromatography, reverse transcription polymerase chain reaction, primer extension, and inosine-specific base cleavage. The most common method for the analysis of editing will be described here. This method involves complete hydrolysis of edited RNAs to nucleoside monophosphates, followed by separation of the products using thin-layer chromatography.

Adenosine↗