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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 December 2022) | Viewed by 41860

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Dr. Naoyuki Kataoka

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Guest Editor

Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences, Graduate School of Agriculture and Life Sciences, Tokyo, Japan
Interests: RNA processing; RNA transport; RNA diseases; hypoxia; epigenetics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Rui Henrique

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Guest Editor

1. Department of Pathology & Cancer Biology and Epigenetics Group, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
2. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
Interests: uropathology; cancer biomarkers; epigenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the updated central dogma, RNAs play pivotal roles in higher eukaryotes. Pre-mRNAs transcribed from genome DNA undergo many processing steps to become mature mRNAs to function as templates for protein synthesis. However, the functions of the mRNA processing step and mRNA are not restricted in protein synthesis. Several lines of evidence demonstrate that they are involved in many biological steps in cells, and their defects result in many diseases in humans.

The focus of this topic is the roles of mRNAs and mRNA-involved biological steps in higher eukaryotes. Examples for this Special Issue include transcriptional regulation, coupling of splicing with mRNA export/localization, nonsense-mediated mRNA decay, translational regulation, and signal transduction pathway modulation by alternative splicing. Manuscripts regarding mRNA metabolic changes during the development of organisms and aberrant splicing in human diseases are also very welcome. The formats for submissions include original research reports, reviews/mini-reviews, perspectives/opinions and methodology articles.

Dr. Naoyuki Kataoka
Prof. Dr. Rui Henrique
Guest Editors

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Keywords

pre-mRNA splicing
transcription
translation
mRNA transport/localization
long non-coding RNA
RNA binding protein
mRNA degradation
RNA diseases

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Published Papers (11 papers)

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Research

Jump to: Review

18 pages, 3544 KiB

Open AccessArticle

DBP7 and YRF1-6 Are Involved in Cell Sensitivity to LiCl by Regulating the Translation of PGM2 mRNA

by Sasi Kumar Jagadeesan, Mustafa Al-gafari, Jiashu Wang, Sarah Takallou, Danielle Allard, Maryam Hajikarimlou, Thomas David Daniel Kazmirchuk, Houman Moteshareie, Kamaledin B. Said, Reza Nokhbeh, Myron Smith, Bahram Samanfar and Ashkan Golshani

Int. J. Mol. Sci. 2023, 24(2), 1785; https://doi.org/10.3390/ijms24021785 - 16 Jan 2023

Cited by 4 | Viewed by 2530

Abstract

Lithium chloride (LiCl) has been widely researched and utilized as a therapeutic option for bipolar disorder (BD). Several pathways, including cell signaling and signal transduction pathways in mammalian cells, are shown to be regulated by LiCl. LiCl can negatively control the expression and activity of PGM2, a phosphoglucomutase that influences sugar metabolism in yeast. In the presence of galactose, when yeast cells are challenged by LiCl, the phosphoglucomutase activity of PGM2p is decreased, causing an increase in the concentration of toxic galactose metabolism intermediates that result in cell sensitivity. Here, we report that the null yeast mutant strains DBP7∆ and YRF1-6∆ exhibit increased LiCl sensitivity on galactose-containing media. Additionally, we demonstrate that DBP7 and YRF1-6 modulate the translational level of PGM2 mRNA, and the observed alteration in translation seems to be associated with the 5′-untranslated region (UTR) of PGM2 mRNA. Furthermore, we observe that DBP7 and YRF1-6 influence, to varying degrees, the translation of other mRNAs that carry different 5′-UTR secondary structures. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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29 pages, 4848 KiB

Open AccessArticle

Transcriptome Analysis of Goat Mammary Gland Tissue Reveals the Adaptive Strategies and Molecular Mechanisms of Lactation and Involution

by Rong Xuan, Jianmin Wang, Xiaodong Zhao, Qing Li, Yanyan Wang, Shanfeng Du, Qingling Duan, Yanfei Guo, Zhibin Ji and Tianle Chao

Int. J. Mol. Sci. 2022, 23(22), 14424; https://doi.org/10.3390/ijms232214424 - 20 Nov 2022

Cited by 8 | Viewed by 2649

Abstract

To understand how genes precisely regulate lactation physiological activity and the molecular genetic mechanisms underlying mammary gland involution, this study investigated the transcriptome characteristics of goat mammary gland tissues at the late gestation (LG), early lactation (EL), peak lactation (PL), late lactation (LL), dry period (DP), and involution (IN) stages. A total of 13,083 differentially expressed transcripts were identified by mutual comparison of mammary gland tissues at six developmental stages. Genes related to cell growth, apoptosis, immunity, nutrient transport, synthesis, and metabolism make adaptive transcriptional changes to meet the needs of mammary lactation. Notably, platelet derived growth factor receptor beta (PDGFRB) was screened as a hub gene of the mammary gland developmental network, which is highly expressed during the DP and IN. Overexpression of PDGFRB in vitro could slow down the G1/S phase arrest of goat mammary epithelial cell cycle and promote cell proliferation by regulating the PI3K/Akt signaling pathway. In addition, PDGFRB overexpression can also affect the expression of genes related to apoptosis, matrix metalloproteinase family, and vascular development, which is beneficial to the remodeling of mammary gland tissue during involution. These findings provide new insights into the molecular mechanisms involved in lactation and mammary gland involution. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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17 pages, 4207 KiB

Open AccessArticle

A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer’s Disease and Mild Cognitive Impairment from Healthy Controls

by Paola Piscopo, Valeria Manzini, Roberto Rivabene, Alessio Crestini, Loredana Le Pera, Elisabetta Pizzi, Caterina Veroni, Giuseppina Talarico, Martina Peconi, Anna Elisa Castellano, Carmelo D’Alessio, Giuseppe Bruno, Massimo Corbo, Nicola Vanacore and Eleonora Lacorte

Int. J. Mol. Sci. 2022, 23(21), 13232; https://doi.org/10.3390/ijms232113232 - 31 Oct 2022

Cited by 10 | Viewed by 2469

Abstract

The most frequently used biomarkers to support the diagnosis of Alzheimer’s Disease (AD) are Aβ42, total-Tau, and phospho-tau protein levels in CSF. Moreover, magnetic resonance imaging is used to assess hippocampal atrophy, 18F-FDG PET to identify abnormal brain metabolism, and PET imaging for amyloid deposition. These tests are rather complex and invasive and not easily applicable to clinical practice. Circulating non-coding RNAs, which are inherently stable and easy to manage, have been reported as promising biomarkers for central nervous system conditions. Recently, circular RNAs (circRNAs) as a novel class of ncRNAs have gained attention. We carried out a pilot study on five participants with AD and five healthy controls (HC) investigating circRNAs by Arraystar Human Circular RNA Microarray V2.0. Among them, 26 circRNAs were differentially expressed (FC ≥ 1.5, p < 0.05) in participants with AD compared to HC. From a top 10 of differentially expressed circRNAs, a validation study was carried out on four up-regulated (hsa_circRNA_050263, hsa_circRNA_403959, hsa_circRNA_003022, hsa_circRNA_100837) and two down-regulated (hsa_circRNA_102049, hsa_circRNA_102619) circRNAs in a larger population. Moreover, five subjects with mild cognitive impairment (MCI) were investigated. The analysis confirmed the upregulation of hsa_circRNA_050263, hsa_circRNA_403959, and hsa_circRNA_003022 both in subjects with AD and in MCI compared to HCs. We also investigated all microRNAs potentially interacting with the studied circRNAs. The GO enrichment analysis shows they are involved in the development of the nervous system, and in the cellular response to nerve growth factor stimuli, protein phosphorylation, apoptotic processes, and inflammation pathways, all of which are processes related to the pathology of AD. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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19 pages, 3883 KiB

Open AccessArticle

Comprehensive Transcriptome Analysis of Hair Follicle Morphogenesis Reveals That lncRNA-H19 Promotes Dermal Papilla Cell Proliferation through the Chi-miR-214-3p/β-Catenin Axis in Cashmere Goats

by Yuelang Zhang, Fang Li, Yujie Shi, Tongtong Zhang and Xin Wang

Int. J. Mol. Sci. 2022, 23(17), 10006; https://doi.org/10.3390/ijms231710006 - 2 Sep 2022

Cited by 10 | Viewed by 2419

Abstract

Cashmere is initiated and develops in the fetal stages and the number and density of secondary hair follicles (SHFs) determine cashmere production and quality. Growing evidence indicates that both microRNA (miRNA) and long non-coding RNA (lncRNA) play an indispensable role in hair follicle (HF) growth and development. However, little is known about miRNAs, lncRNAs, and their functions as well as their interactions during cashmere initiation and development. Here, based on lncRNA and miRNA high-throughput sequencing and bioinformatics analysis, we identified 10,485 lncRNAs, 40,639 mRNAs, and 605 miRNAs in cashmere goat skin during HF induction, organogenesis, and cytodifferentiation stages. Among them, 521 lncRNAs, 5976 genes, and 204 miRNAs were differentially expressed (DE). KEGG analysis of DE genes indicated that ECM–receptor interaction and biosynthesis of amino acids were crucial for HF development. Notch, TGF-beta, and Wnt signaling pathways were also identified, which are conventional pathways associated with HF growth and development. Then, the ceRNA regulatory network was constructed, and the impact of lncRNA H19 was investigated in dermal papilla (DP) cells. The MTT, CCK-8, and EdU assays showed that the viability and proliferation of DP cells were promoted by H19, and mechanistic studies suggested that H19 performed its function through the chi-miR-214-3p/β-catenin axis. The present study created a resource for lncRNA, miRNA, and mRNA studies in cashmere morphogenesis. It could contribute to a better understanding of the molecular mechanism of ncRNAs involved in the regulation of HF growth and development. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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16 pages, 4141 KiB

Open AccessArticle

Effects of Ethanol on Expression of Coding and Noncoding RNAs in Murine Neuroblastoma Neuro2a Cells

by Mi Ran Choi, Sinyoung Cho, Dai-Jin Kim, Jung-Seok Choi, Yeung-Bae Jin, Miran Kim, Hye Jin Chang, Seong Ho Jeon, Young Duk Yang and Sang-Rae Lee

Int. J. Mol. Sci. 2022, 23(13), 7294; https://doi.org/10.3390/ijms23137294 - 30 Jun 2022

Cited by 3 | Viewed by 2400

Abstract

Excessive use of alcohol can induce neurobiological and neuropathological alterations in the brain, including the hippocampus and forebrain, through changes in neurotransmitter systems, hormonal systems, and neuroimmune processes. We aimed to investigate the effects of ethanol on the expression of coding and noncoding RNAs in a brain-derived cell line exposed to ethanol. After exposing Neuro2a cells, a neuroblastoma cell line, to ethanol for 24 and 72 h, we observed cell proliferation and analyzed up- and downregulated mRNAs and long noncoding RNAs (lncRNAs) using total RNA-Seq technology. We validated the differential expression of some mRNAs and lncRNAs by RT-qPCR and analyzed the expression of Cebpd and Rnu3a through knock-down of Cebpd. Cell proliferation was significantly reduced in cells exposed to 100 mM ethanol for 72 h, with 1773 transcripts up- or downregulated by greater than three-fold in ethanol-treated cells compared to controls. Of these, 514 were identified as lncRNAs. Differentially expressed mRNAs and lncRNAs were mainly observed in cells exposed to ethanol for 72 h, in which Atm and Cnr1 decreased, but Trib3, Cebpd, and Spdef increased. On the other hand, lncRNAs Kcnq1ot1, Tug1, and Xist were changed by ethanol, and Rnu3a in particular was greatly increased by chronic ethanol treatment through inhibition of Cebpd. Our results increase the understanding of cellular and molecular mechanisms related to coding and noncoding RNAs in an in vitro model of acute and chronic exposure to ethanol. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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15 pages, 7365 KiB

Open AccessArticle

The miR-106b/NR2F2-AS1/PLEKHO2 Axis Regulates Migration and Invasion of Colorectal Cancer through the MAPK Pathway

by Shuzhen Liu, Guoyan An, Qing Cao, Tong Li, Xinyu Jia and Lei Lei

Int. J. Mol. Sci. 2021, 22(11), 5877; https://doi.org/10.3390/ijms22115877 - 30 May 2021

Cited by 7 | Viewed by 3207

Abstract

Increasing numbers of miRNAs have been observed as oncogenes or tumor suppressors in colorectal cancer (CRC). It was recently reported that hsa-miR-106b-5p (miR-106b) promoted CRC cell migration and invasion. However, there were also studies showing contradictory results. Therefore, in the present study, we further explore the role of miR-106b and its downstream networks in the carcinogenesis of CRC. We observed that the expression of miR-106b is significantly increased in Pan-Cancer and CRC tissues compared with normal tissues from The Cancer Genome Atlas (TCGA) database. Furthermore, we used Transwell, Cell Counting Kit-8, and colony formation assays to clarify that miR-106b promotes the migratory, invasive, and proliferative abilities of CRC cells. For the first time, we systematically screened the target mRNAs and lncRNAs of miR-106b using TCGA database and the bioinformatics algorithms. Dual-luciferase reporter assay confirmed that NR2F2-AS1 and PLEKHO2 are the direct targets of miR-106b. Furthermore, NR2F2-AS1 acts as a competing endogenous RNA (ceRNA) to regulate PLEKHO2 expression by sponging miR-106b. The results of Gene set enrichment analysis (GSEA) and Western blot indicated that they play important roles in CRC progression by regulating MAPK pathway. Thus, miR-106b/NR2F2-AS1/PLEKHO2/MAPK signaling axis may suggest the potential usage in CRC treatment. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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Review

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28 pages, 3431 KiB

Open AccessReview

An Epidemiological Systematic Review with Meta-Analysis on Biomarker Role of Circulating MicroRNAs in Breast Cancer Incidence

by Lisa Padroni, Laura De Marco, Lucia Dansero, Valentina Fiano, Lorenzo Milani, Paolo Vasapolli, Luca Manfredi, Saverio Caini, Claudia Agnoli, Fulvio Ricceri and Carlotta Sacerdote

Int. J. Mol. Sci. 2023, 24(4), 3910; https://doi.org/10.3390/ijms24043910 - 15 Feb 2023

Cited by 3 | Viewed by 2503

Abstract

Breast cancer (BC) is a multifactorial disease caused by an interaction between genetic predisposition and environmental exposures. MicroRNAs are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and seem to be related to cancer risk factors. We conducted a systematic review and meta-analysis to identify circulating microRNAs related to BC diagnosis, paying special attention to methodological problems in this research field. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seventy-five studies were included in the systematic review. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seven studies were included in the MIR21 and MIR155 meta-analysis, while four studies were included in the MIR10b metanalysis. The pooled sensitivity and specificity of MIR21 for BC diagnosis were 0.86 (95%CI 0.76–0.93) and 0.84 (95%CI 0.71–0.92), 0.83 (95%CI 0.72–0.91) and 0.90 (95%CI 0.69–0.97) for MIR155, and 0.56 (95%CI 0.32–0.71) and 0.95 (95%CI 0.88–0.98) for MIR10b, respectively. Several other microRNAs were found to be dysregulated, distinguishing BC patients from healthy controls. However, there was little consistency between included studies, making it difficult to identify specific microRNAs useful for diagnosis. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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18 pages, 1165 KiB

Open AccessReview

The Functional Meaning of 5′UTR in Protein-Coding Genes

by Natalia Ryczek, Aneta Łyś and Izabela Makałowska

Int. J. Mol. Sci. 2023, 24(3), 2976; https://doi.org/10.3390/ijms24032976 - 3 Feb 2023

Cited by 28 | Viewed by 7933

Abstract

As it is well known, messenger RNA has many regulatory regions along its sequence length. One of them is the 5′ untranslated region (5’UTR), which itself contains many regulatory elements such as upstream ORFs (uORFs), internal ribosome entry sites (IRESs), microRNA binding sites, and structural components involved in the regulation of mRNA stability, pre-mRNA splicing, and translation initiation. Activation of the alternative, more upstream transcription start site leads to an extension of 5′UTR. One of the consequences of 5′UTRs extension may be head-to-head gene overlap. This review describes elements in 5′UTR of protein-coding transcripts and the functional significance of protein-coding genes 5′ overlap with implications for transcription, translation, and disease. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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14 pages, 851 KiB

Open AccessReview

Emergent Roles of Circular RNAs in Metabolism and Metabolic Disorders

by Yueh-Lin Wu, Hsiao-Fen Li, Hsi-Hsien Chen and Heng Lin

Int. J. Mol. Sci. 2022, 23(3), 1032; https://doi.org/10.3390/ijms23031032 - 18 Jan 2022

Cited by 12 | Viewed by 5316

Abstract

Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called “back-splicing,” which forms covalently closed continuous loops. Due to their lack of a 5’ cap and 3’ poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body’s homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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16 pages, 2275 KiB

Open AccessReview

Nuclear RNA Exosome and Pervasive Transcription: Dual Sculptors of Genome Function

by Koichi Ogami and Hiroshi I. Suzuki

Int. J. Mol. Sci. 2021, 22(24), 13401; https://doi.org/10.3390/ijms222413401 - 13 Dec 2021

Cited by 10 | Viewed by 6000

Abstract

The genome is pervasively transcribed across various species, yielding numerous non-coding RNAs. As a counterbalance for pervasive transcription, various organisms have a nuclear RNA exosome complex, whose structure is well conserved between yeast and mammalian cells. The RNA exosome not only regulates the processing of stable RNA species, such as rRNAs, tRNAs, small nucleolar RNAs, and small nuclear RNAs, but also plays a central role in RNA surveillance by degrading many unstable RNAs and misprocessed pre-mRNAs. In addition, associated cofactors of RNA exosome direct the exosome to distinct classes of RNA substrates, suggesting divergent and/or multi-layer control of RNA quality in the cell. While the RNA exosome is essential for cell viability and influences various cellular processes, mutations and alterations in the RNA exosome components are linked to the collection of rare diseases and various diseases including cancer, respectively. The present review summarizes the relationships between pervasive transcription and RNA exosome, including evolutionary crosstalk, mechanisms of RNA exosome-mediated RNA surveillance, and physiopathological effects of perturbation of RNA exosome. Full article

(This article belongs to the Special Issue mRNAs in Biology)

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13 pages, 289 KiB

Open AccessReview

The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications

by Anna Puła, Paweł Robak, Damian Mikulski and Tadeusz Robak

Int. J. Mol. Sci. 2021, 22(21), 12070; https://doi.org/10.3390/ijms222112070 - 8 Nov 2021

Cited by 4 | Viewed by 2858

Abstract

Multiple myeloma (MM) is a genetically complex disease that results from a multistep transformation of normal to malignant plasma cells in the bone marrow. However, the molecular mechanisms responsible for the initiation and heterogeneous evolution of MM remain largely unknown. A fundamental step needed to understand the oncogenesis of MM and its response to therapy is the identification of driver mutations. The introduction of gene expression profiling (GEP) in MM is an important step in elucidating the molecular heterogeneity of MM and its clinical relevance. Since some mutations in myeloma occur in non-coding regions, studies based on the analysis of mRNA provide more comprehensive information on the oncogenic pathways and mechanisms relevant to MM biology. In this review, we discuss the role of gene expression profiling in understanding the biology of multiple myeloma together with the clinical manifestation of the disease, as well as its impact on treatment decisions and future directions. Full article

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