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Review
. 2024 Sep 24;10(5):49.
doi: 10.3390/ncrna10050049.

Back to the Origin: Mechanisms of circRNA-Directed Regulation of Host Genes in Human Disease

Haomiao Yuan  1   2   3 , Xizhou Liao  4 , Ding Hu  4 , Dawei Guan  1   2   3 , Meihui Tian  1   2   4
Affiliations
Review

Back to the Origin: Mechanisms of circRNA-Directed Regulation of Host Genes in Human Disease

Haomiao Yuan et al. Noncoding RNA. .

Abstract

Circular RNAs (circRNAs) have been shown to be pivotal regulators in various human diseases by participating in gene splicing, acting as microRNA (miRNA) sponges, interacting with RNA-binding proteins (RBPs), and translating into short peptides. As the back-splicing products of pre-mRNAs, many circRNAs can modulate the expression of their host genes through transcriptional, post-transcriptional, translational, and post-translational control via interaction with other molecules. This review provides a detailed summary of these regulatory mechanisms based on the class of molecules that they interact with, which encompass DNA, mRNA, miRNA, and RBPs. The co-expression of circRNAs with their parental gene productions (including linear counterparts and proteins) provides potential diagnostic biomarkers for multiple diseases. Meanwhile, the different regulatory mechanisms by which circRNAs act on their host genes via interaction with other molecules constitute complex regulatory networks, which also provide noticeable clues for therapeutic strategies against diseases. Future research should explore whether these proven mechanisms can play a similar role in other types of disease and clarify further details about the cross-talk between circRNAs and host genes. In addition, the regulatory relationship between circRNAs and their host genes in circRNA circularization, degradation, and cellular localization should receive further attention.

Keywords: RNA-binding proteins; ceRNA; circular RNA; host gene; regulatory mechanism.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
CircRNAs regulate host genes via interacting with nucleic acid molecules. Several circRNAs could interact with parental DNA sequences to regulate the transcription of their host genes. For example, FECR1 has the ability to attach to the FLI1 promoter and regulate the hypomethylation of FLI1 DNAs (a), while circSMARCA5 can bind to its parental locus, leading to the formation of a circR-loop (circRNA: DNA hybrid), and transcriptional pausing at exon 15 of SMARCA5 (b). CircRNAs interact with parental mRNA and could be divided by whether the binding site is in the translated regions. The upregulated circHOMER1 can correlate with the expression of HOMER1B mRNA by binding to the 3′-UTR of HOMER1B mRNA, thereby inhibiting the HOMER1B expression in post-transcriptional control (c). CircYAP could interact with eIF4G and PABP, along with Yap1 mRNA, ultimately inhibiting YAP1 translation in breast cancer (d); when circRNA and the host mRNA shared the same miRNAs directly, circRNAs could enhance mRNA stability as miRNA sponge, such as circSIRT (f). In addition, some circRNAs can indirectly regulate host gene expression by influencing other downstream transcription factor genes through the ceRNA mechanism, such as circDAB1. It could absorb miR-1270 and miR-944 in BMSCs to upregulate RBPJ expression. As a transcription factor, RBPJ could activate DAB1 transcription, and facilitate cell proliferation and the osteogenic differentiation of BMSC (e).
Figure 2
Figure 2
CircRNAs regulate host gene expression by binding with protein molecules in transcriptional, post-transcriptional, translational, and post-translational control. At the transcriptional level, ecircRNAs in different cellular locations might play various regulation functions. For example, cytoplasmic localized circBRD7 can recruit H3K27 acetylation in the promoter region of the BRD7, increase the transcriptional activation, and boost the expression of BRD in NPC (a). On the contrary, circPLCE1 inhibits the spliceosome assembly on pre-PLCE1 and hinders intron removal by interacting with the SRSF2 protein in the nucleus (b). ciRNA and EIciRNA (such as circTTN and circCUX1) could also bind to BRPs and thus interact with parental DNA sequences to regulate gene transcription (c,d). At the post-transcriptional level, circRNAs that are localized in the nucleus, such as circETS1, could bind to EIF4A3 to block the export of ETS1 mRNA from the nucleus (e), and the others in the cytoplasm, such as circGRM1, circMMP9, and circCOL6A3, could form a circRNA-RBP complex, associating with miRNAs or their translational peptide, resulting in the alteration of parental mRNA stability (f–h). At the translational level, certain circRNAs could hinder the binding of BRP to parental mRNA and impede the translation of host genes, such as circPABPN1 (i). Others like circFBXW7 have the ability to encode a short peptide, which could compete for the binding to USP28 with FBXW7, thus antagonizing the USP28-induced stabilization of c-Myc and c-Jun (j). At the post-translational level, circRNAs could bind or recruit RBPs, thus resulting in the ubiquitination or phosphorylation of the proteins (k–n). Moreover, circCCNB1 could regulate the nuclear translocation of CCNB1 by interacting with CDK1 (o). Furthermore, the rolling translation EGFR (rtEGFR) directly interacts with EGFR, weakening endocytosis and the degradation of EGFR proteins (p).
Figure 3
Figure 3
CircRNAs play crucial roles in the pathogenesis of numerous human diseases by modulating the expression of their host genes. In transcriptional regulation, circRNAs could interact with DNA, miRNAs, and proteins to fulfill their regulation in host genes. In the post-transcriptional, translational, and post-translational regulatory levels, circRNAs fulfill their parental gene regulatory functions in both neoplastic and non-neoplastic diseases mainly by adsorbing miRNAs or binding to proteins. The direct interactions of circRNAs with parental mRNAs are only mentioned in post-transcriptional and translational regulations.
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