Methylxanthines Increase Expression of the Splicing Factor SRSF2 by Regulating Multiple Post-transcriptional Mechanisms

Shi, Jia; Pabon, Kirk; Scotto, Kathleen W.

doi:10.1074/jbc.m114.624254

Cited by 8 publications

(12 citation statements)

References 85 publications

(81 reference statements)

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“…The interplay between trans -factors and corresponding cis -elements within transcripts precisely manipulated tissue- and stage-specific splicing events 6 . Altering expression levels of splicing factors is an efficient and dominant mean to fine-tune alternative splicing profiles 7 8 . It is imperative to obtain comprehensive insights into AS events in the genome-wide era 9 .…”

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confidence: 99%

RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes

Lin

Liu

et al. 2016

Sci Rep

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RNA-binding motif protein 4a (RBM4a) reportedly reprograms splicing profiles of the insulin receptor (IR) and myocyte enhancer factor 2C (MEF2C) genes, facilitating the differentiation of brown adipocytes. Using an RNA-sequencing analysis, we first compared the gene expressing profiles between wild-type and RBM4a−/− brown adipocytes. The ablation of RBM4a led to increases in the PTBP1, PTBP2 (nPTB), and Nova1 proteins, whereas elevated RBM4a reduced the expression of PTBP1 and PTBP2 proteins in brown adipocytes through an alternative splicing-coupled nonsense-mediated decay mechanism. Subsequently, RBM4a indirectly shortened the half-life of the Nova1 transcript which was comparatively stable in the presence of PTBP2. RBM4a diminished the influence of PTBP2 in adipogenic development by reprogramming the splicing profiles of the FGFR2 and PKM genes. These results constitute a mechanistic understanding of the RBM4a-modulated splicing cascade during the brown adipogenesis.

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confidence: 99%

RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes

Lin

Liu

et al. 2016

Sci Rep

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“…Caffeine can be associated with the regulation of miRNA expression. 57 This substance is recognized as a xanthine and a potent antioxidant able to inhibit alterations caused by oxidative stress at the miRNA transcription. The abnormal augment of miRNA expression silences a considerable range of genes and, consequently, deactivates the translation of multiple proteins; in line with this, caffeine seems to act negatively, thus suppressing the silencing.…”

Section: Discussionmentioning

confidence: 99%

“…The abnormal augment of miRNA expression silences a considerable range of genes and, consequently, deactivates the translation of multiple proteins; in line with this, caffeine seems to act negatively, thus suppressing the silencing. 57 The alternative splicing (AS) of pre-miRNA is a fundamental cellular process which links selectively alternated exons in a group producing variants of mRNA of a single gene. 58 More than 90% of human genes undergo alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

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Serum miRNAs are differentially altered by ethanol and caffeine consumption in rats

Martinez

Rossetto

Arantes

et al. 2019

Toxicology Research

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Alcoholism is a multifactorial disease with high risk for dependence determined by genetic background, environmental factors and neuroadaptations. The excessive consumption of this substance is related to psychiatric problems, epilepsy, cardiovascular disease, cirrhosis and cancers. Caffeine is one of the most popular psychostimulants currently consumed in the world. The combination of ethanol and caffeine ingested by consuming “energy drinks” is becoming increasingly popular among young people. We analyzed the effect of simultaneous consumption of ethanol and caffeine on the serum profile of miRNAs differentially expressed in the ethanol-drinking rat model (UChB strain). Adult rats were divided into three groups (n = 5 per group): UChB group (rats fed with 1 : 10 (v/v) ethanol ad libitum); UChB + caffeine group (rats fed with 1 : 10 (v/v) ethanol ad libitum + 3 g L−1 of caffeine); control group (rats drinking water used as the control for UChB). The treatment with caffeine occurred from day 95 to 150 days old, totalizing 55 days of ethanol + caffeine ingestion. The expressions of microRNAs (miR) -9-3p, -15b-5p, -16-5p, -21-5p, -200a-3p and -222-3p were detected by Real Time-PCR (RT-PCR). The expressions of miR-9-3p, -15b-5p, -16-5p and -222-3p were upregulated in the UChB group. Conversely, simultaneous ingestion of ethanol and caffeine significantly reversed these expressions to similar levels to control animals, thus emphasizing that caffeine had a protective effect in the presence of ethanol. In addition, miR-21-5p was downregulated with ethanol consumption whereas miR-222-3p was unchanged. Ethanol and caffeine consumption was capable of altering serum miRNAs, which are potential biomarkers for the systemic effects of these addictive substances.

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“…Because of the biological complexity governing NMD, as well as the fact that NMD may be downregulated in different cell types and cell states, experimental laboratory validation is necessary to determine if an individual IR mRNA is NMD‐sensitive under particular conditions (Hug et al, 2016). The impact of NMD on IR transcripts can be evaluated in cell culture via inhibition of the NMD pathway, either using broad range chemicals such as caffeine or more specifically by knocking down or conditionally knocking out core NMD components such as UPF1 or UPF2 or SMG6 (Colombo, Karousis, Bourquin, Bruggmann, & Muhlemann, 2017; Nicholson, Joncourt, & Muhlemann, 2012; Shi, Pabon, & Scotto, 2015). However, the interpretation of these experiments can be confounded by the fact that NMD triggers a compensation effect called nonsense‐induced transcriptional compensation that often upregulates the expression of genes related to the NMD targets (Ma et al, 2019).…”

Section: Predicting Ir Transcripts That May Be Targeted By Nmdmentioning

confidence: 99%

Intron retention and its impact on gene expression and protein diversity: A review and a practical guide

et al. 2020

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Intron retention (IR) occurs when a complete and unspliced intron remains in mature mRNA. An increasing body of literature has demonstrated a major role for IR in numerous biological functions, including several that impact human health and disease. Although experimental technologies used to study other forms of mRNA splicing can also be used to investigate IR, a specialized downstream computational analysis is optimal for IR discovery and analysis. Here we provide a review of IR and its biological implications, as well as a practical guide for how to detect and analyze it. Several methods, including long read third generation direct RNA sequencing, are described. We have developed an R package, FakIR, to facilitate the execution of the bioinformatic tasks recommended in this review and a tutorial on how to fit them to users aims. Additionally, we provide guidelines and experimental protocols to validate IR discovery and to evaluate the potential impact of IR on gene expression and protein output. This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA Processing > Splicing Regulation/Alternative Splicing RNA Methods > RNA Analyses in vitro and In Silico K E Y W O R D S intron retention, nonsense mediated decay, post-transcriptional gene regulation, RNA export, RNA processing 1 | INTRODUCTION Alternative splicing of messenger RNA (mRNA) is responsible for much of the proteome complexity in mammals (Berget, Moore, & Sharp, 2000; Nilsen & Graveley, 2010). We now know that at least 90% of all mammalian genes can undergo some form of alternative splicing, often generating multiple protein isoforms with sometimes disparate biological functions (Wang et al., 2008). Intron retention (IR) is a type of alternative splicing that is gaining increased interest in human health and disease research. Originally described in plants and viruses, IR has now been shown to be a common form of alternative David F. Grabski, Lucile Broseus, and Bandana Kumari contributed equally to this study.

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Methylxanthines Increase Expression of the Splicing Factor SRSF2 by Regulating Multiple Post-transcriptional Mechanisms

Cited by 8 publications

References 85 publications

RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes

RBM4a-regulated splicing cascade modulates the differentiation and metabolic activities of brown adipocytes

Serum miRNAs are differentially altered by ethanol and caffeine consumption in rats

Intron retention and its impact on gene expression and protein diversity: A review and a practical guide

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