Natural Antisense Transcripts As Versatile Regulators of Gene Expression

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2024 Apr 17

PMID 38632496

Authors

Andreas Werner

Aditi Kanhere

Claes Wahlestedt

John S Mattick

Affiliations

Soon will be listed here.

Abstract

Long non-coding RNAs (lncRNAs) are emerging as a major class of gene products that have central roles in cell and developmental biology. Natural antisense transcripts (NATs) are an important subset of lncRNAs that are expressed from the opposite strand of protein-coding and non-coding genes and are a genome-wide phenomenon in both eukaryotes and prokaryotes. In eukaryotes, a myriad of NATs participate in regulatory pathways that affect expression of their cognate sense genes. Recent developments in the study of NATs and lncRNAs and large-scale sequencing and bioinformatics projects suggest that whether NATs regulate expression, splicing, stability or translation of the sense transcript is influenced by the pattern and degrees of overlap between the sense-antisense pair. Moreover, epigenetic gene regulatory mechanisms prevail in somatic cells whereas mechanisms dependent on the formation of double-stranded RNA intermediates are prevalent in germ cells. The modulating effects of NATs on sense transcript expression make NATs rational targets for therapeutic interventions.

Citing Articles

Mechanism of expression regulation of head-to-head overlapping protein-coding genes INO80E and HIRIP3.

Ryczek N, Lys A, Wanowska E, Kozlowska-Maslon J, Makalowska I Commun Biol. 2025; 8(1):391.

PMID: 40057624 PMC: 11890862. DOI: 10.1038/s42003-025-07815-4.

Comprehensive Mapping of Human dsRNAome Reveals Conservation, Neuronal Enrichment, and Intermolecular Interactions.

Andrews R, Bass B bioRxiv. 2025; .

PMID: 39975386 PMC: 11838218. DOI: 10.1101/2025.01.24.634786.

An antisense-long-noncoding-RNA modulates p75 expression levels during neuronal polarization.

De Paolis V, Paolillo N, Siri T, Grosso A, Lorello V, Spina C iScience. 2025; 28(1):111566.

PMID: 39811648 PMC: 11730960. DOI: 10.1016/j.isci.2024.111566.

CDH3-AS1 antisense RNA enhances P-cadherin translation and acts as a tumor suppressor in melanoma.

Chadourne M, Griffith C, Xu X, Brennan E, Vera O, Mecozzi N bioRxiv. 2025; .

PMID: 39764055 PMC: 11703152. DOI: 10.1101/2024.12.26.630428.

Localization is the key to action: regulatory peculiarities of lncRNAs.

Poloni J, Oliveira F, Feltes B Front Genet. 2024; 15:1478352.

PMID: 39737005 PMC: 11683014. DOI: 10.3389/fgene.2024.1478352.

References

Mattick J, Amaral P, Carninci P, Carpenter S, Chang H, Chen L . Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol. 2023; 24(6):430-447. PMC: 10213152. DOI: 10.1038/s41580-022-00566-8. View

Nordstrom K, WAGNER E, Persson C, Blomberg P, Ohman M . Translational control by antisense RNA in control of plasmid replication. Gene. 1988; 72(1-2):237-40. DOI: 10.1016/0378-1119(88)90148-5. View

Lipman D . Making (anti)sense of non-coding sequence conservation. Nucleic Acids Res. 1997; 25(18):3580-3. PMC: 146938. DOI: 10.1093/nar/25.18.3580. View

Fahey M, Moore T, Higgins D . Overlapping antisense transcription in the human genome. Comp Funct Genomics. 2008; 3(3):244-53. PMC: 2447278. DOI: 10.1002/cfg.173. View

Shendure J, Church G . Computational discovery of sense-antisense transcription in the human and mouse genomes. Genome Biol. 2002; 3(9):RESEARCH0044. PMC: 126869. DOI: 10.1186/gb-2002-3-9-research0044. View

Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M . Antisense transcription in the mammalian transcriptome. Science. 2005; 309(5740):1564-6. DOI: 10.1126/science.1112009. View

Kiyosawa H, Yamanaka I, Osato N, Kondo S, Hayashizaki Y . Antisense transcripts with FANTOM2 clone set and their implications for gene regulation. Genome Res. 2003; 13(6B):1324-34. PMC: 403655. DOI: 10.1101/gr.982903. View

Pillay S, Takahashi H, Carninci P, Kanhere A . Antisense RNAs during early vertebrate development are divided in groups with distinct features. Genome Res. 2021; 31(6):995-1010. PMC: 8168585. DOI: 10.1101/gr.262964.120. View

Arnold M, Stengel K . Emerging insights into enhancer biology and function. Transcription. 2023; 14(1-2):68-87. PMC: 10353330. DOI: 10.1080/21541264.2023.2222032. View

10.

Barral A, Dejardin J . The chromatin signatures of enhancers and their dynamic regulation. Nucleus. 2023; 14(1):2160551. PMC: 9828845. DOI: 10.1080/19491034.2022.2160551. View

11.

Yamanaka Y, Faghihi M, Magistri M, Alvarez-Garcia O, Lotz M, Wahlestedt C . Antisense RNA controls LRP1 Sense transcript expression through interaction with a chromatin-associated protein, HMGB2. Cell Rep. 2015; 11(6):967-976. PMC: 4431949. DOI: 10.1016/j.celrep.2015.04.011. View

12.

Cawley S, Bekiranov S, Ng H, Kapranov P, Sekinger E, Kampa D . Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell. 2004; 116(4):499-509. DOI: 10.1016/s0092-8674(04)00127-8. View

13.

Burd C, Jeck W, Liu Y, Sanoff H, Wang Z, Sharpless N . Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet. 2010; 6(12):e1001233. PMC: 2996334. DOI: 10.1371/journal.pgen.1001233. View

14.

Hansen T, Wiklund E, Bramsen J, Villadsen S, Statham A, Clark S . miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011; 30(21):4414-22. PMC: 3230379. DOI: 10.1038/emboj.2011.359. View

15.

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A . Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013; 495(7441):333-8. DOI: 10.1038/nature11928. View

16.

Ma J, Du W, Zeng K, Wu N, Fang L, Lyu J . An antisense circular RNA circSCRIB enhances cancer progression by suppressing parental gene splicing and translation. Mol Ther. 2021; 29(9):2754-2768. PMC: 8417507. DOI: 10.1016/j.ymthe.2021.08.002. View

17.

Zhang H, Liu S, Li X, Yao L, Wu H, Baluska F . An Antisense Circular RNA Regulates Expression of RuBisCO Small Subunit Genes in . Front Plant Sci. 2021; 12:665014. PMC: 8181130. DOI: 10.3389/fpls.2021.665014. View

18.

Wight M, Werner A . The functions of natural antisense transcripts. Essays Biochem. 2013; 54:91-101. PMC: 4284957. DOI: 10.1042/bse0540091. View

19.

Vangoor V, Gomes-Duarte A, Pasterkamp R . Long non-coding RNAs in motor neuron development and disease. J Neurochem. 2020; 156(6):777-801. PMC: 8048821. DOI: 10.1111/jnc.15198. View

20.

Salzman J, Gawad C, Wang P, Lacayo N, Brown P . Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012; 7(2):e30733. PMC: 3270023. DOI: 10.1371/journal.pone.0030733. View