J Lipid Atheroscler.  2020 Jan;9(1):8-22. 10.12997/jla.2020.9.1.8.

mTOR-coordinated Post-Transcriptional Gene Regulations: from Fundamental to Pathogenic Insights

• Yeh HS
• Yong J

• KMID: 2470798
• DOI: http://doi.org/10.12997/jla.2020.9.1.8

Abstract

Post-transcriptional regulations of mRNA transcripts such as alternative splicing and alternative polyadenylation can affect the expression of genes without changing the transcript levels. Recent studies have demonstrated that these post-transcriptional events can have significant physiological impacts on various biological systems and play important roles in the pathogenesis of a number of diseases, including cancers. Nevertheless, how cellular signaling pathways control these post-transcriptional processes in cells are not very well explored in the field yet. The mammalian target of rapamycin complex 1 (mTORC1) pathway plays a key role in sensing cellular nutrient and energy status and regulating the proliferation and growth of cells by controlling various anabolic and catabolic processes. Dysregulation of mTORC1 pathway can tip the metabolic balance of cells and is associated with a number of pathological conditions, including various types of cancers, diabetes, and cardiovascular diseases. Numerous reports have shown that mTORC1 controls its downstream pathways through translational and/or transcriptional regulation of the expression of key downstream effectors. And, recent studies have also shown that mTORC1 can control downstream pathways via post-transcriptional regulations. In this review, we will discuss the roles of post-transcriptional processes in gene expression regulations and how mTORC1-mediated post-transcriptional regulations contribute to cellular physiological changes. We highlight post-transcriptional regulation as an additional layer of gene expression control by mTORC1 to steer cellular biology. These emphasize the importance of studying post-transcriptional events in transcriptome datasets for gaining a fuller understanding of gene expression regulations in the biological systems of interest.

Keyword

Polyadenylation; Alternative splicing; Mammalian target of rapamycin; Gene expression; Transcriptome

MeSH Terms

Alternative Splicing
Cardiovascular Diseases
Dataset
Gene Expression
Polyadenylation
RNA, Messenger
Sirolimus
Social Control, Formal*
Transcriptome
RNA, Messenger
Sirolimus

Figure

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  Fig. 1 Overview of post-transcriptional regulations in eukaryotic cells. (A) Co-transcriptional events and transcriptional termination. Post-transcriptional processing, i.e. splicing, polyadenylation, AS, and APA occur co-transcriptionally. These post-transcriptional events can produce transcript isoforms from genes and contribute to the diversity and dynamics of the transcriptome and the resulting proteome. (B) The 5 different types of AS events. (C) The 2 types of APA events. The 3′-UTRs serve as binding platforms of various regulatory RBPs and miRNAs (upper). UTR-APA, since most of the alternative PASs are proximal, 3′-UTRs are often shortened, resulting in the production of transcripts that can escape the regulation of those regulatory factors. The 2 types of CR-APA (lower). P, promoter; Pol II, polymerase II; PAS, poly-A signal; 5′-P, 5′ phosphate group; Xrn2, 5′-3′ exoribonuclease 2; UTR, untranslated region; CDS, coding DNA sequences; CR, coding region; APA, alternative polyadenylation; SS, splice site; RBP, RNA-binding protein.

• 

  Fig. 2 Illustration of mTORC1's translational and transcriptional controls over various metabolic pathways and physiological outcomes. The activation of mTORC1 not only leads to the upregulation of cellular translation activity, but also regulates various metabolic pathways through controlling transcription networks. mTORC1, mammalian target of rapamycin complex 1; HIF-1, hypoxia-inducible factor 1; Nrf2, nuclear factor erythroid 2-related factor 2; HSF1, heat shock factor 1; NF-κB, nuclear factor kappa B; STAT3, signal transducer and activator of transcription-3; ATF4, activating transcription factor 4; PPAR, peroxisome proliferator-activated receptor γ; SREBP-1, sterol regulatory element binding protein 1; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1 alpha; mTOR, mammalian target of rapamycin; PRAS40, proline-rich Akt substrate of 40 kDa; PP2A, protein phosphatase 2A; TIF-1A, transcription initiation factor 1A; Atg, autophagy-related; ULK, Unc-51-like kinase; 4E-BP, 4E-binding protein; eIF4G, eukaryotic translation initiation factor 4G.

• 

  Fig. 3 Illustration of how mTORC1-mediated post-transcriptional regulations play a role in controlling various cellular pathways and physiological outcomes. Recent studies have shown that mTORC1 controls the AS and APA of select genes, affecting their expressions. These can lead to changes in cellular biology, e.g. proliferation. mTORC1, mammalian target of rapamycin complex 1; AS, alternative splicing; APA, alternative polyadenylation; mTOR, mammalian target of rapamycin; PRAS40, proline-rich Akt substrate of 40 kDa; U2AF1, U2 small nuclear RNA auxiliary factor 1; S6K1, S6 kinase beta-1; SRPK2, serine and arginine rich splicing factor protein kinase 2; SR, serine arginine; UTR, untranslated region; DGE, differential gene expression; ER, endoplasmic reticulum.

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