Abstract
Long non-coding RNAs (lncRNAs) outnumber protein-coding transcripts, but their functions remain largely unknown. In this Review, we discuss the emerging roles of lncRNAs in the control of gene transcription. Some of the best characterized lncRNAs have essential transcription cis-regulatory functions that cannot be easily accomplished by DNA-interacting transcription factors, such as XIST, which controls X-chromosome inactivation, or imprinted lncRNAs that direct allele-specific repression. A growing number of lncRNA transcription units, including CHASERR, PVT1 and HASTER (also known as HNF1A-AS1) act as transcription-stabilizing elements that fine-tune the activity of dosage-sensitive genes that encode transcription factors. Genetic experiments have shown that defects in such transcription stabilizers often cause severe phenotypes. Other lncRNAs, such as lincRNA-p21 (also known as Trp53cor1) and Maenli (Gm29348) contribute to local activation of gene transcription, whereas distinct lncRNAs influence gene transcription in trans. We discuss findings of lncRNAs that elicit a function through either activation of their transcription, transcript elongation and processing or the lncRNA molecule itself. We also discuss emerging evidence of lncRNA involvement in human diseases, and their potential as therapeutic targets.
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Acknowledgements
The authors thank T. Graff, M. Cuenca-Ardura and B. Payer for critical reading of this manuscript. This work was supported by European Research Council (789055) and Spanish Ministry of Science and Innovation (PID2021-122522OB-I00) grants to J.F., and by National Institute of Health (R01CA262286 and R37CA230580) grants to N.D.
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Glossary
- CpG islands
-
Genomic regions of 500 nucleotides or longer with >50% CpG dinucleotide repeat content. CpG islands are associated with the transcription start sites of most housekeeping genes and as many as 40% of tissue-specific genes; they are bound by regulatory proteins.
- CTCF
-
A zinc-finger transcription factor (TF), also known as CCCTC-binding factor, that binds specific DNA sequences and participates in the formation of chromatin loops that influence gene transcription by defining the boundaries of topologically associated domains (TADs) and bringing enhancers into proximity with promoters.
- DNA–DNA–RNA triplex
-
A structure in which single-stranded RNA invades the major groove of double-stranded DNA and binds by forming Hoogsteen hydrogen bonds. DNA–DNA–lncRNA triplexes can be identified by pull-downs with a triplex-specific antibody.
- Enhancer RNAs
-
(eRNAs). Non-coding RNAs that are bidirectionally transcribed from enhancer regions, and are typically ≤500 nucleotides and unstable (half-life ≤ 2 min).
- Enhancers
-
Genomic regions that are recognized by transcription factors (TFs) and activate and increase the transcription of genes in cis, sometimes from considerable distances. Active enhancers are flanked by nucleosomes that carry post-translational histone modifications such as histone H3 acetylated at lysine 27 (H3K27ac) and H3 methylated at lysine 4 (H3K4me1).
- Expression quantitative trait loci
-
(eQTL). Genetic loci in which different alleles of a DNA variant influence expression levels of coding or non-coding transcripts.
- Focal deletions
-
Cancer-associated genomic deletions smaller than 5 Mb that affect both alleles.
- Genome-wide association studies
-
(GWAS). Studies that survey DNA variants genome-wide to identify those showing association with a disease or trait. GWAS have been used to discover susceptibility variants for prevalent polygenic diseases. A large fraction of significant associations are found in non-coding genomic regions, indicating that they are mediated by genetic variants that influence regulatory functions.
- lncRNAs that act in cis
-
Long non-coding RNAs (lncRNAs) that act on the same chromosome from which they are transcribed, including the regulation of a neighbouring gene, of multiple genes or of the entire chromosome.
- Silencers
-
Genomic regions that are bound by repressive transcription factors (TFs) and decrease the transcription of genes in cis.
- Splicing quantitative trait loci
-
Genetic loci in which different alleles influence RNA splicing patterns.
- Topologically associated domains
-
(TADs). Genomic regions defined by having a higher frequency of long-range chromatin contacts, such as between genes and their regulatory elements, than the frequency of contacts with elements outside the region.
- Transcriptional condensates
-
Chromatin-associated, dynamic nuclear assemblies comprising a heterogeneous mix of RNAs, transcription factors (TFs) and co-regulators that modulate transcriptional output.
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Ferrer, J., Dimitrova, N. Transcription regulation by long non-coding RNAs: mechanisms and disease relevance. Nat Rev Mol Cell Biol 25, 396–415 (2024). https://doi.org/10.1038/s41580-023-00694-9
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DOI: https://doi.org/10.1038/s41580-023-00694-9
