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Molecular Mechanisms of mRNA Transcriptional Regulation

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

Deadline for manuscript submissions: closed (10 May 2023) | Viewed by 19362

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Special Issue Editor

Dr. Andrey Turchinovich

E-Mail Website1 Website2
Guest Editor

1. Department of Cardiovascular Research, Heidelberg University, 69117 Heidelberg, Germany
2. Heidelberg Biolabs GmbH, 69120 Heidelberg, Germany
Interests: regulation of gene expression; non-coding RNA; cell-free RNA; cancer biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Regulation of mRNA transcription is a highly dynamic process mediated by various molecular events which include specific DNA–protein, RNA–protein, RNA-RNA as well as DNA–RNA interactions. This complex process can be controlled at several steps, including the initial recruitment and assembly of the transcriptional machinery, transcription initiation, transcription pausing, transcription elongation, as well as termination phases. In addition, regulation of mRNA biogenesis and degradation involves the participation of various non-coding RNAs (ncRNAs), such as microRNAs, endogenous siRNAs, small nuclear RNAs, long ncRNAs, circular RNAs, and enhancer RNAs. This Special Issue focuses on the roles of different classes of RNAs and proteins regulating mRNA expression in various cell types. In particular, studies involving advanced deep sequencing, proteomics, and novel bioinformatics algorithms for RNA research are highly welcomed. The formats for submission include original research reports, reviews, and communications.

Dr. Andrey Turchinovich
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

transcriptoion factors (TFs)
cis-regulatory elements (CREs)
long non-coding RNAs (lncRNAs)
short non-coding RNAs (sncRNAs)
small nuclear RNAs (snRNAs)
microRNA (miRNA)
circular RNA (circRNA)
DNA methylation
chromatin regulators

Related Special Issue

Molecular Mechanisms of mRNA Transcriptional Regulation: 2nd Edition in International Journal of Molecular Sciences (5 articles)

Published Papers (11 papers)

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Research

19 pages, 7088 KiB

Open AccessArticle

REST Targets JAK–STAT and HIF-1 Signaling Pathways in Human Down Syndrome Brain and Neural Cells

by Tan Huang, Sharida Fakurazi, Pike-See Cheah and King-Hwa Ling

Int. J. Mol. Sci. 2023, 24(12), 9980; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24129980 - 10 Jun 2023

Cited by 1 | Viewed by 1425

Abstract

Down syndrome (DS) is the most frequently diagnosed chromosomal disorder of chromosome 21 (HSA21) aneuploidy, characterized by intellectual disability and reduced lifespan. The transcription repressor, Repressor Element-1 Silencing Transcription factor (REST), which acts as an epigenetic regulator, is a crucial regulator of neuronal and glial gene expression. In this study, we identified and investigated the role of REST-target genes in human brain tissues, cerebral organoids, and neural cells in Down syndrome. Gene expression datasets generated from healthy controls and DS samples of human brain tissues, cerebral organoids, NPC, neurons, and astrocytes were retrieved from the Gene Ontology (GEO) and Sequence Read Archive (SRA) databases. Differential expression analysis was performed on all datasets to produce differential expression genes (DEGs) between DS and control groups. REST-targeted DEGs were subjected to functional ontologies, pathways, and network analyses. We found that REST-targeted DEGs in DS were enriched for the JAK–STAT and HIF-1 signaling pathways across multiple distinct brain regions, ages, and neural cell types. We also identified REST-targeted DEGs involved in nervous system development, cell differentiation, fatty acid metabolism and inflammation in the DS brain. Based on the findings, we propose REST as the critical regulator and a promising therapeutic target to modulate homeostatic gene expression in the DS brain. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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21 pages, 8429 KiB

Open AccessArticle

Genome-Wide Expression Analysis of Long Noncoding RNAs and Their Target Genes in Metafemale Drosophila

by Xinyu Liu, Ran Yan, Haosheng Liu, Shuai Zhang, Ruixue Wang, Bowen Zhang and Lin Sun

Int. J. Mol. Sci. 2023, 24(9), 8381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098381 - 06 May 2023

Cited by 1 | Viewed by 1714

Abstract

Aneuploidy is usually more detrimental than altered ploidy of the entire set of chromosomes. To explore the regulatory mechanism of gene expression in aneuploidy, we analyzed the transcriptome sequencing data of metafemale Drosophila. The results showed that most genes on the X chromosome undergo dosage compensation, while the genes on the autosomal chromosomes mainly present inverse dosage effects. Furthermore, long noncoding RNAs (lncRNAs) have been identified as key regulators of gene expression, and they are more sensitive to dosage changes than mRNAs. We analyzed differentially expressed mRNAs (DEGs) and differentially expressed lncRNAs (DELs) in metafemale Drosophila and performed functional enrichment analyses of DEGs and the target genes of DELs, and we found that they are involved in several important biological processes. By constructing lncRNA-mRNA interaction networks and calculating the maximal clique centrality (MCC) value of each node in the network, we also identified two key candidate lncRNAs (CR43940 and CR42765), and two of their target genes, Sin3A and MED1, were identified as inverse dosage modulators. These results suggest that lncRNAs play an important role in the regulation of genomic imbalances. This study may deepen the understanding of the gene expression regulatory mechanisms in aneuploidy from the perspective of lncRNAs. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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16 pages, 4952 KiB

Open AccessArticle

Spleen Transcriptome Profiling Reveals Divergent Immune Responses to LPS and Poly (I:C) Challenge in the Yellow Drum (Nibea albiflora)

by Xiang Zhao, Yuan Zhang, Tianxiang Gao and Na Song

Int. J. Mol. Sci. 2023, 24(9), 7735; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24097735 - 23 Apr 2023

Viewed by 1267

Abstract

The yellow drum (Nibea albiflora) is a marine teleost fish with strong disease resistance, yet the understanding of its immune response and key functional genes is fragmented. Here, RNA-Seq was used to investigate the regulation pathways and genes involved in the immune response to infection with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly (I:C)) on the spleen of the yellow drum. There were fewer differentially expressed genes (DEGs) in the LPS-infected treatment group at either 6 or 48 h. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs were mainly significantly enriched in c5-branching dibasic acid metabolic and complement and coagulation cascades pathways. The yellow drum responded more strongly to poly (I:C) infection, with 185 and 521 DEGs obtained under 6 and 48 h treatments, respectively. These DEGs were significantly enriched in the Toll-like receptor signaling pathway, RIG-I-like receptor signaling pathway, Jak-STAT signaling pathway, NOD-like signaling pathway, and cytokine–cytokine receptor interaction. The key functional genes in these pathways played important roles in the immune response and maintenance of immune system homeostasis in the yellow drum. Weighted gene co-expression network analysis (WGCNA) revealed several important hub genes. Although the functions of some genes have not been confirmed, our study still provides significant information for further investigation of the immune system of the yellow drum. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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18 pages, 2261 KiB

Open AccessArticle

Analysis of RNA Polyadenylation in Healthy and Osteoarthritic Human Articular Cartilage

by Phaedra Winstanley-Zarach, Gregor Rot, Shweta Kuba, Aibek Smagul, Mandy J. Peffers and Simon R. Tew

Int. J. Mol. Sci. 2023, 24(7), 6611; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24076611 - 01 Apr 2023

Viewed by 1752

Abstract

Polyadenylation (polyA) defines the 3′ boundary of a transcript’s genetic information. Its position can vary and alternative polyadenylation (APA) transcripts can exist for a gene. This causes variance in 3′ regulatory domains and can affect coding sequence if intronic events occur. The distribution of polyA sites on articular chondrocyte transcripts has not been studied so we aimed to define their transcriptome-wide location in age-matched healthy and osteoarthritic knee articular cartilage. Total RNA was isolated from frozen tissue samples and analysed using the QuantSeq-Reverse 3′ RNA sequencing approach, where each read runs 3′ to 5′ from within the polyA tail into the transcript and contains a distinct polyA site. Differential expression of transcripts was significant altered between healthy and osteoarthritic samples with enrichment for functionalities that were strongly associated with joint pathology. Subsequent examination of polyA site data allowed us to define the extent of site usage across all the samples. When comparing healthy and osteoarthritic samples, we found that differential use of polyadenylation sites was modest. However, in the genes affected, there was potential for the APA to have functional relevance. We have characterised the polyadenylation landscape of human knee articular chondrocytes and conclude that osteoarthritis does not elicit a widespread change in their polyadenylation site usage. This finding differentiates knee osteoarthritis from pathologies such as cancer where APA is more commonly observed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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16 pages, 3566 KiB

Open AccessArticle

Transcriptome and DNA Methylome Analysis of Two Contrasting Rice Genotypes under Salt Stress during Germination

by Yongqiang Li and Dianjing Guo

Int. J. Mol. Sci. 2023, 24(4), 3978; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043978 - 16 Feb 2023

Cited by 4 | Viewed by 1804

Abstract

With climate change and labor shortages, direct-seeding rice cultivation is becoming popular worldwide, especially in Asia. Salinity stress negatively affects rice seed germination in the direct-seeding process, and the cultivation of suitable direct-seeding rice varieties under salinity stress is necessary. However, little is known about the underlying mechanism of salt responses during seed germination under salt stress. To investigate the salt tolerance mechanism at the seed germination stage, two contrasting rice genotypes differing in salt tolerance, namely, FL478 (salt-tolerant) and IR29 (salt-sensitive), were used in this study. We observed, that compared to IR29, FL478 appeared to be more tolerant to salt stress with a higher germination rate. GD1 (germination defective 1), which was involved in seed germination by regulating alpha-amylase, was upregulated significantly in the salt-sensitive IR29 strain under salt stress during germination. Transcriptomic data showed that salt-responsive genes tended to be up/downregulated in IR29 but not in FL478. Furthermore, we investigated the epigenetic changes in FL478 and IR29 during germination under saline treatment using whole genome bisulfite DNA sequencing (BS-seq) technology. BS-seq data showed that the global CHH methylation level increased dramatically under salinity stress in both strains, and the hyper CHH differentially methylated regions (DMRs) were predominantly located within the transposable elements regions. Compared with FL478, differentially expressed genes with DMRs in IR29 were mainly related to gene ontology terms such as response to water deprivation, response to salt stress, seed germination, and response to hydrogen peroxide pathways. These results may provide valuable insights into the genetic and epigenetic basis of salt tolerance at the seed germination stage, which is important for direct-seeding rice breeding. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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19 pages, 7016 KiB

Open AccessArticle

In Silico Pan-Cancer Analysis Reveals Prognostic Role of the Erythroferrone (ERFE) Gene in Human Malignancies

by Qingyu Xu, Eva Altrock, Nanni Schmitt, Alexander Streuer, Felicitas Rapp, Verena Nowak, Julia Obländer, Nadine Weimer, Iris Palme, Melda Göl, Wolf-Karsten Hofmann, Daniel Nowak and Vladimir Riabov

Int. J. Mol. Sci. 2023, 24(2), 1725; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24021725 - 15 Jan 2023

Viewed by 2117

Abstract

The erythroferrone gene (ERFE), also termed CTRP15, belongs to the C1q tumor necrosis factor-related protein (CTRP) family. Despite multiple reports about the involvement of CTRPs in cancer, the role of ERFE in cancer progression is largely unknown. We previously found that ERFE was upregulated in erythroid progenitors in myelodysplastic syndromes and strongly predicted overall survival. To understand the potential molecular interactions and identify cues for further functional investigation and the prognostic impact of ERFE in other malignancies, we performed a pan-cancer in silico analysis utilizing the Cancer Genome Atlas datasets. Our analysis shows that the ERFE mRNA is significantly overexpressed in 22 tumors and affects the prognosis in 11 cancer types. In certain tumors such as breast cancer and adrenocortical carcinoma, ERFE overexpression has been associated with the presence of oncogenic mutations and a higher tumor mutational burden. The expression of ERFE is co-regulated with the factors and pathways involved in cancer progression and metastasis, including activated pathways of the cell cycle, extracellular matrix/tumor microenvironment, G protein-coupled receptor, NOTCH, WNT, and PI3 kinase-AKT. Moreover, ERFE expression influences intratumoral immune cell infiltration. Conclusively, ERFE is aberrantly expressed in pan-cancer and can potentially function as a prognostic biomarker based on its putative functions during tumorigenesis and tumor development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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14 pages, 3204 KiB

Open AccessArticle

Ssc-miR-92b-3p Regulates Porcine Trophoblast Cell Proliferation and Migration via the PFKM Gene

by Yongzhong Wang, Chen Zhou, Fanming Meng, Qun Hu, Yue Ding, Xiaoliang Wang, Ting Gu, Zicong Li, Zhenfang Wu, Linjun Hong and Gengyuan Cai

Int. J. Mol. Sci. 2022, 23(24), 16138; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416138 - 17 Dec 2022

Viewed by 1645

Abstract

Embryo implantation, the pivotal stage of gestation, is fundamentally dependent on synchronous embryonic development and uterine receptivity. In the early gestation period, the uterus and conceptus secrete growth factors, cytokines, and hormones to promote implantation. Circulating exosomal miRNAs are potential indicators of normal or complicated gestation. Our previous study revealed that pregnant sows’ serum exosomes had upregulated miR-92b-3p expression compared to non-pregnant sows, and that the expression level progressively increased during early gestation. The present study’s findings indicate that, compared to the ninth day of the estrous cycle (C9), pregnant sows had upregulated miR-92b-3p expression in the endometrium and embryos during the implantation stage ranging from day 9 to day 15 of gestation. Additionally, our results demonstrate that miR-92b-3p promotes the proliferation and migration of Porcine Trophoblast Cells (PTr2). Dual-Luciferase Reporter (DLR) gene assay, real-time fluorescent quantitative PCR (RT-qPCR), and Western blotting (WB) confirmed the bioinformatics prediction that phosphofructokinase-M (PFKM) serves as a target gene of miR-92b-3p. Notably, interference of PFKM gene expression markedly promoted PTr2 proliferation and migration. Furthermore, mice with downregulated uterine miR-92b-3p expression had smaller rates of successful embryo implantation. In summary, miR-92b-3p putatively modulates embryo implantation by promoting PTr2 proliferation and migration via its target gene PFKM. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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16 pages, 2850 KiB

Open AccessArticle

Circular Sponge against miR-21 Enhances the Antitumor Activity of Doxorubicin against Breast Cancer Cells

by Ana R. Rama, Patricia Lara, Cristina Mesas, Francisco Quiñonero, Celia Vélez, Consolación Melguizo and Jose Prados

Int. J. Mol. Sci. 2022, 23(23), 14803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232314803 - 26 Nov 2022

Cited by 2 | Viewed by 1574

Abstract

Breast cancer is the most common type of cancer in women, with chemotherapy being the main strategy. However, its effectiveness is reduced by drug resistance mechanisms. miR-21 is upregulated in breast cancer that has been linked to drug resistance and carcinogenic processes. Our aim was to capture miR-21 with a circular sponge (Circ-21) and thus inhibit the carcinogenic processes and drug resistance mechanisms in which it participates. Proliferation, migration, colony formation, cell cycle, and poly [ADP-ribose] polymerase 1 (PARP-1) and vascular endothelial growth factor (VEGF) detection assays were performed with MCF7 breast cancer cells and MCF10A non-tumor cells. In addition, doxorubicin resistance tests and detection of drug resistance gene expression were performed in MCF7 cells. Reduction in proliferation, as well as migration and colony formation, increased PARP-1 expression, inhibition of VEGF expression and cell cycle arrest in G2/M phase were displayed in the Circ-21 MCF7, which were not observed in the MCF10A cells. Furthermore, in the MCF7 cells, the Circ-21 enhanced the antitumor activity of doxorubicin and decreased the expression of resistance genes: ABCA1, ABCC4, and ABCC5. Based on these results, the use of Circ-21 can be considered a first step for the establishment of an effective gene therapy in the treatment of breast cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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14 pages, 1658 KiB

Open AccessArticle

Integrating Single-Cell Transcriptome and Network Analysis to Characterize the Therapeutic Response of Chronic Myeloid Leukemia

by Jialu Ma, Nathan Pettit, John Talburt, Shanzhi Wang, Sherman M. Weissman and Mary Qu Yang

Int. J. Mol. Sci. 2022, 23(22), 14335; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214335 - 18 Nov 2022

Cited by 1 | Viewed by 1787

Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by a unique BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) were developed to target the BCR-ABL oncoprotein, inhibiting its abnormal kinase activity. TKI treatments have significantly improved CML patient outcomes. However, the patients can develop drug resistance and relapse after therapy discontinues largely due to intratumor heterogeneity. It is critical to understand the differences in therapeutic responses among subpopulations of cells. Single-cell RNA sequencing measures the transcriptome of individual cells, allowing us to differentiate and analyze individual cell populations. Here, we integrated a single-cell RNA sequencing profile of CML stem cells and network analysis to decipher the mechanisms of distinct TKI responses. Compared to normal hematopoietic stem cells, a set of genes that were concordantly differentially expressed in various types of stem cells of CML patients was revealed. Further transcription regulatory network analysis found that most of these genes were directly controlled by one or more transcript factors and the genes have more regulators in the cells of the patients who responded to the treatment. The molecular markers including a known drug-resistance gene and novel gene signatures for treatment response were also identified. Moreover, we combined protein–protein interaction network construction with a cancer drug database and uncovered the drugs that target the marker genes directly or indirectly via the protein interactions. The gene signatures and their interacted proteins identified by this work can be used for treatment response prediction and lead to new strategies for drug resistance monitoring and prevention. Our single-cell-based findings offered novel insights into the mechanisms underlying the therapeutic response of CML. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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12 pages, 3220 KiB

Open AccessArticle

Genistein Promotes Skeletal Muscle Regeneration by Regulating miR-221/222

by Linyuan Shen, Tianci Liao, Jingyun Chen, Jianfeng Ma, Jinyong Wang, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Changjun Zeng, Mailin Gan and Li Zhu

Int. J. Mol. Sci. 2022, 23(21), 13482; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113482 - 03 Nov 2022

Cited by 3 | Viewed by 1583

Abstract

Genistein (GEN), a phytoestrogen, has been reported to regulate skeletal muscle endocrine factor expression and muscle fiber type switching, but its role in skeletal muscle regeneration is poorly understood. As a class of epigenetic regulators widely involved in skeletal muscle development, microRNAs (miRNAs) have the potential to treat skeletal muscle injury. In this study, we identified miR-221 and miR-222 and their target genes MyoG and Tnnc1 as key regulators during skeletal muscle regeneration, and both were regulated by GEN. C2C12 myoblasts and C2C12 myotubes were then used to simulate the proliferation and differentiation of muscle satellite cells during skeletal muscle regeneration. The results showed that GEN could inhibit the proliferation of satellite cells and promote the differentiation of satellite cells by inhibiting the expression of miR-221/222. Subsequent in vitro and in vivo experiments showed that GEN improved skeletal muscle regeneration mainly by promoting satellite cell differentiation in the middle and late stages, by regulating miR-221/222 expression. These results suggest that miR-221/222 and their natural regulator GEN have potential applications in skeletal muscle regeneration. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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18 pages, 5478 KiB

Open AccessArticle

Integrated Metabolites and Transcriptomics at Different Growth Stages Reveal Polysaccharide and Flavonoid Biosynthesis in Cynomorium songaricum

by Jie Wang, Hongyan Su, Zhibo Wu, Wenshu Wang, Yubi Zhou and Mengfei Li

Int. J. Mol. Sci. 2022, 23(18), 10675; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810675 - 14 Sep 2022

Cited by 2 | Viewed by 1562

Abstract

Cynomorium songaricum is a perennial parasitic herb, and its stem is widely used as a traditional Chinese medicine, which largely relies on bioactive compounds (e.g., polysaccharides, flavonoids, and triterpenes). To date, although the optimum harvest time of stems has been demonstrated at the unearthed stage (namely the early flowering stage, EFS), the accumulation mechanism of polysaccharides and flavonoids during growth stages is still limited. In this study, the physiological characteristics (stem fresh weight, contents of soluble sugar and flavonoids, and antioxidant capacity) at four different growth stages (germination stage (GS), vegetative growth stage (VGS), EFS, and flowering stage (FS)) were determined, transcriptomics were analyzed by illumina sequencing, and expression levels of key genes were validated by qRT-PCR at the GS, VGS, and EFS. The results show that the stem biomass, soluble sugar and total flavonoids contents, and antioxidant capacity peaked at EFS compared with GS, VGS, and FS. A total of 6098 and 13,023 differentially expressed genes (DEGs) were observed at VGS and EFS vs. GS, respectively, with 367 genes co-expressed. Based on their biological functions, 109 genes were directly involved in polysaccharide and flavonoid biosynthesis as well as growth and development. The expression levels of key genes involved in polysaccharides (e.g., GLCs, XTHs and PMEs), flavonoids (e.g., 4CLLs, CYPs and UGTs), growth and development (e.g., AC58, TCPs and AP1), hormones biosynthesis and signaling (e.g., YUC8, AIPT and ACO1), and transcription factors (e.g., MYBs, bHLHs and WRKYs) were in accordance with changes of physiological characteristics. The combinational analysis of metabolites with transcriptomics provides insight into the mechanism of polysaccharide and flavonoid biosynthesis in C. songaricum during growth stages. Full article

(This article belongs to the Special Issue Molecular Mechanisms of mRNA Transcriptional Regulation)

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