Functional Micropeptides Encoded by Long Non-Coding RNAs: A Comprehensive Review

Pan, Jianfeng; Wang, Ruijun; Shang, Fangzheng; Ma, Rong; Rong, Youjun; Zhang, Yanjun

doi:10.3389/fmolb.2022.817517

Cited by 26 publications

(15 citation statements)

References 136 publications

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“…We expect translational repression mediated by CRISPRδ to have several advantages over preexisting methods. A wide array of studies have reported small but functional micropeptides encoded by long noncoding RNAs 157 , 158 , which were originally expected to contain no protein-coding regions. Moreover, mRNAs have been reported to have protein coding-independent functions 159 – 161 .…”

Section: Discussionmentioning

confidence: 99%

dCas13-mediated translational repression for accurate gene silencing in mammalian cells

Apostolopoulos,

Kawamoto,

Chow

et al. 2024

Nat Commun

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Current gene silencing tools based on RNA interference (RNAi) or, more recently, clustered regularly interspaced short palindromic repeats (CRISPR)‒Cas13 systems have critical drawbacks, such as off-target effects (RNAi) or collateral mRNA cleavage (CRISPR‒Cas13). Thus, a more specific method of gene knockdown is needed. Here, we develop CRISPRδ, an approach for translational silencing, harnessing catalytically inactive Cas13 proteins (dCas13). Owing to its tight association with mRNA, dCas13 serves as a physical roadblock for scanning ribosomes during translation initiation and does not affect mRNA stability. Guide RNAs covering the start codon lead to the highest efficacy regardless of the translation initiation mechanism: cap-dependent, internal ribosome entry site (IRES)-dependent, or repeat-associated non-AUG (RAN) translation. Strikingly, genome-wide ribosome profiling reveals the ultrahigh gene silencing specificity of CRISPRδ. Moreover, the fusion of a translational repressor to dCas13 further improves the performance. Our method provides a framework for translational repression-based gene silencing in eukaryotes.

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Section: Discussionmentioning

confidence: 99%

dCas13-mediated translational repression for accurate gene silencing in mammalian cells

Apostolopoulos,

Kawamoto,

Chow

et al. 2024

Nat Commun

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“…Studies have also shown that many conserved lncRNAs encode micropeptides. 40 For example, HoxB-AS1 was found to harbor two potential micropeptides of 15 and 61 amino acids, respectively. 30 However, in vitro translation assays for the corresponding mouse sequences did not detect any protein products from either of these two ORFs, which indicates that Hoxb3os is noncoding.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease

Weisser,

Eckberg,

D'Amico

et al. 2023

JASN

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Background: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder characterized by the formation of kidney cysts and is primarily caused by mutations in two genes, PKD1 and PKD2. Methods: In this study, we investigated the role of the long noncoding RNA (lncRNA) Hoxb3os in ADPKD by ablating its expression in the mouse. Results: Hoxb3os-null mice were viable and had grossly normal kidney morphology but displayed activation of mTOR/Akt signaling and subsequent increase in kidney cell proliferation. To determine the role of Hoxb3os in cystogenesis, we crossed the Hoxb3os-null mouse to two orthologous Pkd1 mouse models: Pkhd1/Cre;Pkd1 F/F (rapid cyst progression) and Pkd1 RC/RC (slow cyst progression). Ablation of Hoxb3os exacerbated cyst growth in both models. To gain insight into the mechanism whereby Hoxb3os inhibition promotes cystogenesis, we performed western blot analysis of mTOR/Akt pathway between Pkd1 single-knockout (SKO) and Pkd1-Hoxb3os double-knockout (DKO) mice. Compared to SKO, DKO mice presented with enhanced levels of total and phosphorylated Rictor. This was accompanied by increased phosphorylation of Akt at Ser473, a known mTORC2 effector site. Physiologically, kidneys from DKO mice displayed between 50-60% increase in cell proliferation and cyst number. Conclusion: Results from this study indicate that ablation of Hoxb3os in mouse PKD exacerbates cystogenesis and dysregulates mTORC2.

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“…Considering that mt-Shlp6 was found to be dynamically regulated in brown adipose tissue of the thirteen-lined ground squirrel across hibernation states ( Figure 4 ), the existence of ASncmtRNA-1 and ASncmtRNA-2 in hibernating model species and their abundance changes during daily torpor or the stages of hibernation are of special interest ( Burzio et al, 2009 ). They should also be analysed with regard to the finding that most long non-coding RNAs contain sORFs, hence, the potential to encode functional micropeptides ( Pan et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial polymorphism m.3017C>T of SHLP6 relates to heterothermy

Emser,

Spielvogel,

Millesi

et al. 2023

Front. Physiol.

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Heterothermic thermoregulation requires intricate regulation of metabolic rate and activation of pro-survival factors. Eliciting these responses and coordinating the necessary energy shifts likely involves retrograde signalling by mitochondrial-derived peptides (MDPs). Members of the group were suggested before to play a role in heterothermic physiology, a key component of hibernation and daily torpor. Here we studied the mitochondrial single-nucleotide polymorphism (SNP) m.3017C>T that resides in the evolutionarily conserved gene MT-SHLP6. The substitution occurring in several mammalian orders causes truncation of SHLP6 peptide size from twenty to nine amino acids. Public mass spectrometric (MS) data of human SHLP6 indicated a canonical size of 20 amino acids, but not the use of alternative translation initiation codons that would expand the peptide. The shorter isoform of SHLP6 was found in heterothermic rodents at higher frequency compared to homeothermic rodents (p < 0.001). In heterothermic mammals it was associated with lower minimal body temperature (Tb, p < 0.001). In the thirteen-lined ground squirrel, brown adipose tissue—a key organ required for hibernation, showed dynamic changes of the steady-state transcript level of mt-Shlp6. The level was significantly higher before hibernation and during interbout arousal and lower during torpor and after hibernation. Our finding argues to further explore the mode of action of SHLP6 size isoforms with respect to mammalian thermoregulation and possibly mitochondrial retrograde signalling.

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Functional Micropeptides Encoded by Long Non-Coding RNAs: A Comprehensive Review

Cited by 26 publications

References 136 publications

dCas13-mediated translational repression for accurate gene silencing in mammalian cells

dCas13-mediated translational repression for accurate gene silencing in mammalian cells

Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease

Mitochondrial polymorphism m.3017C>T of SHLP6 relates to heterothermy

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