ReviewTiming without coding: How do long non-coding RNAs regulate circadian rhythms?
Introduction
A central dogma in biology describes that genetic information embedded in DNA is passed on to a protein, whereas RNA is simply an intermediate molecule that transfers genetic information. Therefore, it came as a surprise to find that up to 80% of genomes are actively transcribed, yet, only about 2% of the genome is used to encode a protein in humans [1], [2]. Transcripts that do not have the potential to encode a protein are called “non-coding” RNAs (ncRNAs), and are considered to be particularly important for the complexity of the organism as the ratio of ncRNA to total genome size significantly increases in higher eukaryotes [3], [4]. Some ncRNAs have been well-characterized and have been shown to exert important functions. For example, rRNA and tRNA are required for mRNA translation, while small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) are essential for splicing and RNA modification, respectively [5], [6]. New classes of ncRNAs, such as microRNAs (miRNAs), enhancer RNAs (eRNAs), and circular RNAs (circRNAs), also have a variety of regulatory roles [5], [6]. These ncRNAs can be divided into short- or long ncRNAs (lncRNAs) using the arbitrary cutoff of 200 nt [7].
LncRNAs can be categorized by their genomic location and orientation in relation to nearby protein coding genes [8], [9] (Fig. 1). They were originally considered background transcription noise and to lack defined functions, mainly because of their low expression level and the lack of conservation in their primary sequences [10], [11], [12], [13], [14]. More recent studies, however, discovered conservation in their genomic positions (synteny), promoter sequence, and secondary structure, suggesting that lncRNAs carry important genetic information without relying solely on their sequence [13], [14], [15]. In fact, studies in the past decade have found that lncRNAs elicit a wide spectrum of functions in diverse biological processes such as X inactivation, cell differentiation, and neuronal or immune functions as well as disease development including cancer, neurodegeneration, and congenital genetic diseases [16], [17].
Recent studies have also underscored the importance of lncRNAs in regulating circadian rhythms. Although it is still in its infancy, some studies found hundreds of lncRNAs whose expression is either rhythmic or induced by the activation of cyclic AMP (cAMP) pathway, implicating their functions in the circadian clock system (Table 1) [18], [19], [20], [21]. Other studies found a more direct link between lncRNAs and the circadian clock and demonstrated that lncRNAs regulate core clock genes and the core machinery (Table 2). In this review, we discuss: (1) How is the transcription of lncRNA regulated?, (2) How can lncRNAs regulate target genes without encoding a protein?, and (3) Are the functions of lncRNAs in the circadian clock system evolutionarily conserved?, while highlighting the differences and similarities between lncRNAs and mRNAs.
Section snippets
Are there circadian lncRNAs?
LncRNAs are fundamentally different from mRNAs in their capacity to encode a protein. At the same time, they share interesting similarities and differences to mRNAs in their structure, functions, and regulatory mechanisms. Almost all lncRNAs are transcribed by RNA Polymerase II (RNAP II) and modified with a 5′cap similar to mRNAs. However, only ~50% of lncRNAs have a poly(A) tail [13], [22], [23]. Nearly all lncRNAs are also spliced, although the number of exons are much fewer in lncRNAs [10],
Functions of lncRNAs: how can lncRNAs exert their functions without making a protein?
The advent of next-generation sequencing technologies has led to the discovery of a number of lncRNAs as discussed in the previous section [2], [10], [11], [12], [13], [14], [22], [25], however, the function of most remains unknown. This is mainly because of the lack of a systematic strategy in predicting the functions of lncRNAs based on their sequence or structure. Instead, empirical approaches, such as ‘guilt by association,’ can help infer function as well as potential interacting partners
Evolutionary conservation of lncRNAs in the circadian clock system
The molecular architecture of core clock mechanisms is highly conserved from fungi to animals and consists of positive and negative regulators forming a negative feedback loop (Fig. 3) [64], [65], [66]. Interestingly, natural antisense transcripts (RNAs transcribed from the opposite strand of a coding gene locus, Fig. 1) for a negative regulator have been found in a few different species (Fig. 3). The sense-antisense genomic arrangement intuitively suggests that they regulate each other and
Conclusion and future perspectives
LncRNAs have attracted significant interest from the scientific community in the past decade and remarkable progress has been made in discovering thousands of lncRNAs as well as deciphering their function in various biological processes. Circadian rhythm is no exception and hundreds of lncRNAs have now been shown to either be rhythmically expressed or regulate the behavior of the core clock genes and the core machinery (Table 1). These numbers, however, are most likely underestimated, as
Acknowledgment
Work in the Kojima Lab is supported by R01GM126223 from the National Institute of Health (NIH) (to Shihoko Kojima). The authors thank Dr. Janet Webster for critical reading of our manuscript, as well as the members of the Kojima Lab for useful discussion and feedback.
References (82)
- et al.
Non-coding RNA regulatory networks
Biochim Biophys. Acta Gene Regul. Mech.
(2020) - et al.
Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species
Cell Rep.
(2015) - et al.
Physiological roles of long noncoding RNAs: insight from knockout mice
Trends Cell Biol.
(2014) - et al.
Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome
Cell Metab.
(2012) - et al.
Rhythms of the genome: circadian dynamics from chromatin topology, tissue-specific gene expression, to behavior
Trends Genet.
(2018) - et al.
Light-induced resetting of a mammalian circadian clock is associated with rapid induction of the mPer1 transcript
Cell
(1997) - et al.
Cycling transcriptional networks optimize energy utilization on a genome scale
Cell Rep.
(2015) - et al.
Characteristics of antisense transcript promoters and the regulation of their activity
Int. J. Mol. Sci.
(2015) - et al.
Lateral thinking: how histone modifications regulate gene expression
Trends Genet.
(2016) Linking long noncoding RNA localization and function
Trends Biochem Sci.
(2016)
Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA
Gastroenterology
A long noncoding RNA perturbs the circadian rhythm of hepatoma cells to facilitate hepatocarcinogenesis
Neoplasia
The role of a lncRNA (TCONS_00044595) in regulating pineal CLOCK expression after neonatal hypoxia-ischemia brain injury
Biochem Biophys. Res Commun.
The role of miR-182 in regulating pineal CLOCK expression after hypoxia-ischemia brain injury in neonatal rats
Neurosci. Lett.
Long non-coding RNA profiling in a non-alcoholic fatty liver disease rodent model: new insight into pathogenesis
Int. J. Mol. Sci.
Emerging roles of non-coding RNA transcription
Trends Biochem. Sci.
Molecular bases for circadian clocks
Cell
Circadian clock neurons in the silkmoth Antheraea pernyi: novel mechanisms of Period protein regulation
Neuron
How a circadian clock adapts to seasonal decreases in temperature and day length
Neuron
Analysis of human Per4
Brain Res. Mol. Brain Res.
Emerging roles of non-coding RNA transcription
Trends Biochem Sci.
Genome-scale CRISPR-mediated control of gene repression and activation
Cell
Physiological roles of long noncoding RNAs: insight from knockout mice
Trends Cell Biol.
Finishing the euchromatic sequence of the human genome
Nature
Landscape of transcription in human cells
Nature
History, discovery, and classification of lncRNAs
Adv. Exp. Med. Biol.
RNA regulation: a new genetics?
Nat. Rev. Genet.
Non-coding RNA
Hum. Mol. Genet.
Visiting “Noncodarnia”
BioTechniques
Antisense transcription in the mammalian transcriptome
Science
RNA maps reveal new RNA classes and a possible function for pervasive transcription
Science
Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses
Genes Dev.
Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells
Proc. Natl. Acad. Sci. U. S. A.
Ab initio reconstruction of cell type-specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs
Nat. Biotechnol.
The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression
Genome Res.
The evolution of lncRNA repertoires and expression patterns in tetrapods
Nature
Reverse-genetics studies of lncRNAs-what we have learnt and paths forward
Genome Biol.
A circadian gene expression atlas in mammals: implications for biology and medicine
Proc. Natl. Acad. Sci. U. S. A.
A class of circadian long non-coding RNAs mark enhancers modulating long-range circadian gene regulation
Nucleic Acids Res.
Circadian changes in long noncoding RNAs in the pineal gland
Proc. Natl. Acad. Sci. U. S. A.
Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals
Nature
Cited by (8)
Long non-coding RNAs mediate fish gene expression in response to ocean acidification
2024, Evolutionary ApplicationsClinical study on the role of LncRNA STX17-AS1 in wound healing and hypertrophic scar formation
2024, International Wound JournalNovel Insights into the Circadian Rhythms Based on Long Noncoding and Circular RNA Profiling
2024, International Journal of Molecular SciencesMicrobial circadian clocks: host-microbe interplay in diel cycles
2023, BMC Microbiology