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

ABSTRACT: 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.

SUBMITTER: Sun M

PROVIDER: S-EPMC1243798 | biostudies-other | 2005

REPOSITORIES: biostudies-other

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

Sun Miao M Hurst Laurence D LD Carmichael Gordon G GG Chen Jianjun J

Nucleic acids research 20051004 17

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. ...[more]

PMID: 16204454

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Project description:BackgroundIn spite of large intergenic spaces in plant and animal genomes, 7% to 30% of genes in the genomes encode overlapping cis-natural antisense transcripts (cis-NATs). The widespread occurrence of cis-NATs suggests an evolutionary advantage for this type of genomic arrangement. Experimental evidence for the regulation of two cis-NAT gene pairs by natural antisense transcripts-generated small interfering RNAs (nat-siRNAs) via the RNA interference (RNAi) pathway has been reported in Arabidopsis. However, the extent of siRNA-mediated regulation of cis-NAT genes is still unclear in any genome.ResultsThe hallmarks of RNAi regulation of NATs are 1) inverse regulation of two genes in a cis-NAT pair by environmental and developmental cues and 2) generation of siRNAs by cis-NAT genes. We examined Arabidopsis transcript profiling data from public microarray databases to identify cis-NAT pairs whose sense and antisense transcripts show opposite expression changes. A subset of the cis-NAT genes displayed negatively correlated expression profiles as well as inverse differential expression changes under at least one of the examined developmental stages or treatment conditions. By searching the Arabidopsis Small RNA Project (ASRP) and Massively Parallel Signature Sequencing (MPSS) small RNA databases as well as our stress-treated small RNA dataset, we found small RNAs that matched at least one gene in 646 pairs out of 1008 (64%) protein-coding cis-NAT pairs, which suggests that siRNAs may regulate the expression of many cis-NAT genes. 209 putative siRNAs have the potential to target more than one gene and half of these small RNAs could target multiple members of a gene family. Furthermore, the majority of the putative siRNAs within the overlapping regions tend to target only one transcript of a given NAT pair, which is consistent with our previous finding on salt- and bacteria-induced nat-siRNAs. In addition, we found that genes encoding plastid- or mitochondrion-targeted proteins are over-represented in the Arabidopsis cis-NATs and that 19% of sense and antisense partner genes of cis-NATs share at least one common Gene Ontology term, which suggests that they encode proteins with possible functional connection.ConclusionThe negatively correlated expression patterns of sense and antisense genes as well as the presence of siRNAs in many of the cis-NATs suggest that siRNA regulation of cis-NATs via the RNAi pathway is an important gene regulatory mechanism for at least a subgroup of cis-NATs in Arabidopsis.

Project description:BACKGROUND: Cis-natural antisense transcripts (cis-NATs) are RNAs transcribed from the antisense strand of a gene locus, and are complementary to the RNA transcribed from the sense strand. Common techniques including microarray approach and analysis of transcriptome databases are the major ways to globally identify cis-NATs in various eukaryotic organisms. Genome-wide in silico analysis has identified a large number of cis-NATs that may generate endogenous short interfering RNAs (nat-siRNAs), which participate in important biogenesis mechanisms for transcriptional and post-transcriptional regulation in rice. However, the transcriptomes are yet to be deeply sequenced to comprehensively investigate cis-NATs. RESULTS: We applied high-throughput strand-specific complementary DNA sequencing technology (ssRNA-seq) to deeply sequence mRNA for assessing sense and antisense transcripts that were derived under salt, drought and cold stresses, and normal conditions, in the model plant rice (Oryza sativa). Combined with RAP-DB genome annotation (the Rice Annotation Project Database build-5 data set), 76,013 transcripts corresponding to 45,844 unique gene loci were assembled, in which 4873 gene loci were newly identified. Of 3819 putative rice cis-NATs, 2292 were detected as expressed and giving rise to small RNAs from their overlapping regions through integrated analysis of ssRNA-seq data and small RNA data. Among them, 503 cis-NATs seemed to be associated with specific conditions. The deep sequence data from isolated epidermal cells of rice seedlings further showed that 54.0% of cis-NATs were expressed simultaneously in a population of homogenous cells. Nearly 9.7% of rice transcripts were involved in one-to-one or many-to-many cis-NATs formation. Furthermore, only 17.4-34.7% of 223 many-to-many cis-NAT groups were all expressed and generated nat-siRNAs, indicating that only some cis-NAT groups may be involved in complex regulatory networks. CONCLUSIONS: Our study profiles an abundance of cis-NATs and nat-siRNAs in rice. These data are valuable for gaining insight into the complex function of the rice transcriptome.

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

Publications

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

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