# Cis-natural antisense transcript
A cis-natural antisense transcript (cis-NAT) is an endogenous RNA transcribed from the DNA strand opposite to another gene at the same genomic locus, so that it overlaps its sense partner and, in the absence of [RNA editing](https://www.edgepedia.org/rna-editing), displays perfect sequence complementarity to it[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5796072/). Cis-NATs are one of two classes of natural antisense transcript (NAT); the other class, trans-NATs, are transcribed from different loci and form short, imperfect matches with several targets[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/). Most cis-NATs are long noncoding RNAs, and the most frequent pairing is one protein-coding transcript with an antisense non-protein-coding transcript[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC8490965/).
| Key fact | Detail |
|---|---|
| Definition | Transcribed from the opposite strand of the same genomic locus as its sense partner, with perfect RNA–RNA complementarity (absent RNA editing)[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC5796072/) |
| Overlap classes | Head-to-head (5′ to 5′), tail-to-tail (3′ to 3′), or fully overlapping; tail-to-tail is the most prevalent orientation in all genome-wide studies except one[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/) |
| Prevalence | Potentially generated by up to 22%–26% of human genes, 22%–29% of mouse genes, 15%–17% of fly genes, 0.5%–2.8% of worm genes, 9% of Arabidopsis genes, 11% of yeast genes, and 12% of Plasmodium falciparum genes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/) |
| Processing | Transcribed by RNA polymerase II and show mRNA-like hallmarks including splicing, a poly-A tail, and a cap structure[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC4284957/) |
| Regulatory reach | Implicated in translation initiation, mRNA stability, transcription termination, alternative splicing, RNA editing, DNA methylation, histone methylation, siRNA-induced silencing, and translational enhancement[6](https://www.nature.com/articles/s41467-020-19186-x) |
| Functional characterization | Only around 70 functional NATs have been reported despite genome-scale transcriptomic data[7](https://pubmed.ncbi.nlm.nih.gov/27894947/) |
## Definition and classification
Natural antisense transcripts are endogenous RNA molecules containing sequences complementary to other transcripts. The cis/trans distinction rests on the site of biogenesis: cis-NATs come from opposing DNA strands at the same locus, trans-NATs from separate loci. Because of their genomic overlap, cis-NAT pairs form long perfect matches with a single antisense partner, whereas trans-NATs mostly form short imperfect matches with several partners and can build complex regulation networks[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/).
**Overlap geometry.** Cis-NAT pairs are categorized by their relative orientation and degree of overlap: head-to-head pairs overlap at their 5′ ends, tail-to-tail pairs at their 3′ ends, and fully overlapping pairs place one transcript entirely within the region of the other[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/). A convergent (3′-end overlap), divergent (5′-end overlap), and enclosed (one transcript encompassing the other) scheme describes the same three types[6](https://www.nature.com/articles/s41467-020-19186-x). All genome-wide studies except one have reported the tail-to-tail orientation as the most prevalent[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/).
## Prevalence
Genome sequencing and annotation suggest that overlapping gene pairs able to generate cis-NATs are widespread in eukaryotes: up to 22%–26% of human genes, 22%–29% of mouse genes, 15%–17% of fly genes, 0.5%–2.8% of worm genes, 9% of [Arabidopsis](https://www.edgepedia.org/arabidopsis) genes, 11% of yeast genes, and 12% of [Plasmodium falciparum](https://www.edgepedia.org/plasmodium-falciparum) genes[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/). Broader measures of antisense transcription are larger still: genome-wide analyses indicate that 60%–80% of the human genome, more than 70% of the mouse genome, and around 30% of plant genomes produce antisense transcripts[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/), and around 15% of human protein-encoding genes have an associated NAT[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/).
**Convergent promoters.** A substantial share of antisense transcription downstream of promoters arises from convergent promoter pairs. In mammalian genomes, convergent promoters comprise about a quarter of all active transcript start sites and initiate 5′-overlapping antisense RNAs, an RNA class previously believed to be rare; within these cis-regulatory domains, transcription factors can regulate both constituent promoters by binding to only one of them[8](https://www.nature.com/articles/s41588-024-02025-w).
## Mechanisms of regulation
Cis-NATs act at nearly all stages of gene expression, from pre-transcriptional through transcriptional and post-transcriptional to translation, and can modulate gene expression positively or negatively[7](https://pubmed.ncbi.nlm.nih.gov/27894947/). Reported mechanisms include RNA masking, alternative splicing, genomic imprinting, chromatin remodeling, and RNA editing[9](https://www.tandfonline.com/doi/pdf/10.1080/15476286.2017.1356564?needAccess=true), as well as effects on translation initiation, mRNA stability, transcription termination, [DNA methylation](https://www.edgepedia.org/dna-methylation), histone methylation, and translational enhancement[6](https://www.nature.com/articles/s41467-020-19186-x).
**Small interfering RNAs.** When overlapping sense and antisense transcripts are expressed at the same time in the same cell, they can form double-stranded RNA that is recognized by the small RNA biogenesis machinery and processed into small interfering RNAs (nat-siRNAs). In plants, siRNAs show an overall sixfold enrichment in the overlapping regions of cis-NATs, and 19%–29% of siRNA-generating cis-NATs give rise to siRNAs only in their overlapping regions[1](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/). In animals and plants, however, relatively few examples of siRNA-mediated effects for cis-NATs have been described relative to the number of potential pairs, indicating that this mechanism may be less frequently used than initially thought[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC6501089/).
**Protein sequestration.** A 2025 study of the cancer cell adhesion gene ICAM1 found that its mRNA interacts with its antisense transcript (ICAM1-AS) to form a long double-stranded RNA that entraps the ILF2/[ILF3](https://www.edgepedia.org/ilf3) complex, preventing these factors from transcribing target genes including the translation initiation factor [EIF4E](https://www.edgepedia.org/eif4e) and reducing global protein translation[11](https://www.sciencedirect.com/science/article/abs/pii/S1097276525010160).
**Translational enhancement.** SINEUPs are antisense long noncoding RNAs that enhance the translation of overlapping sense mRNAs in trans through two domains: an antisense binding domain providing target specificity and an invSINEB2 effector domain that up-regulates translation[12](https://academic.oup.com/nar/article/53/15/gkaf788/8237242).
## Examples in plants
Plant genomes provide characterized cis-NAT cases tied to environmental response. Natural antisense transcripts of MIR398 genes suppress microR398 processing and attenuate plant thermotolerance[6](https://www.nature.com/articles/s41467-020-19186-x). In tomato, a cis-natural antisense RNA regulates alternative polyadenylation of SlSPX5 under phosphate starvation[13](https://www.nature.com/articles/s41467-025-63406-1).
## Detection
Detecting cis-NATs requires methods that preserve strand orientation. Earlier high-throughput approaches included SAGE-derived techniques, microarrays, and tiling arrays; strand-specific RNA sequencing has since become the widely adopted genome-scale method. After reads are mapped to a reference genome, transcripts are classified as antisense by a program that verifies whether detected reads overlap annotated genes transcribed from the opposite strand, and protein-coding potential is then assessed to distinguish coding from noncoding RNAs. Nascent-RNA methods such as global run-on sequencing (GRO-seq), native elongating transcript sequencing (NET-seq), and sequencing of short metabolically labeled RNA have also been used to detect unstable antisense transcripts[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC9569758/).
## History and open scope
Cis-NATs were first detected in viruses in 1976, then in prokaryotes, and finally in eukaryotes[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/). Originally considered transcriptional noise arising from so-called junk DNA, they are now recognized as important modulators of gene regulation[7](https://pubmed.ncbi.nlm.nih.gov/27894947/). The gap between predicted and characterized activity remains large: against thousands of predicted pairs, only around 70 functional NATs have been reported, which limits comprehensive understanding of the field[7](https://pubmed.ncbi.nlm.nih.gov/27894947/). Antisense transcripts also have evolutionary potential beyond regulation: modeling work indicates antisense transcripts can evolve to encode novel proteins[15](https://www.nature.com/articles/s41467-024-50550-3).
## References
1. [Mechanisms of Small RNA Generation from Cis-NATs in Response to Environmental and Developmental Cues (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC3660955/)
2. [Natural Antisense Transcripts: Molecular Mechanisms and Implications in Breast Cancers (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC5796072/)
3. [Overlapping genes in natural and engineered genomes (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8490965/)
4. [Genome-wide natural antisense transcription: coupling its regulation to its different regulatory mechanisms (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC1794690/)
5. [The functions of natural antisense transcripts (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC4284957/)
6. [Natural antisense transcripts of MIR398 genes suppress microR398 processing and attenuate plant thermotolerance, Nature Communications](https://www.nature.com/articles/s41467-020-19186-x)
7. [Strategies to identify natural antisense transcripts (PubMed)](https://pubmed.ncbi.nlm.nih.gov/27894947/)
8. [Gene regulation by convergent promoters, Nature Genetics](https://www.nature.com/articles/s41588-024-02025-w)
9. [Natural antisense transcripts drive a regulatory cascade controlling c-MYC transcription](https://www.tandfonline.com/doi/pdf/10.1080/15476286.2017.1356564?needAccess=true)
10. [Control of Cognate Sense mRNA Translation by cis-Natural Antisense RNAs (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC6501089/)
11. [ICAM1 mRNA entraps ILF2/ILF3 to inhibit transcription of EIF4E and global protein synthesis, Molecular Cell](https://www.sciencedirect.com/science/article/abs/pii/S1097276525010160)
12. [Internal ribosome entry sites enhance translation in trans in antisense non-coding SINEUP and circular RNAs, Nucleic Acids Research](https://academic.oup.com/nar/article/53/15/gkaf788/8237242)
13. [A cis-natural antisense RNA regulates alternative polyadenylation of SlSPX5 under Pi starvation in tomato, Nature Communications](https://www.nature.com/articles/s41467-025-63406-1)
14. [Antisense Transcription in Plants: A Systematic Review and an Update on cis-NATs of Sugarcane (PMC)](https://pmc.ncbi.nlm.nih.gov/articles/PMC9569758/)
15. [How antisense transcripts can evolve to encode novel proteins, Nature Communications](https://www.nature.com/articles/s41467-024-50550-3)
---
*Topic: Encyclopedia › Life and health › Biological foundations › RNA and gene regulation › Long and structural non-coding RNAs › Antisense RNAs › Natural antisense transcript biology*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license