Non-coding RNA-mediated Regulation Research Articles

EPIGENETIC MODIFICATIONS OF STRESS-RELATED DISORDERS: MECHANISMS, IMPLICATIONS AND THERAPEUTIC PERSPECTIVES

Stress-related disorders, encompassing conditions such as anxiety, depression, and post-traumatic stress disorder (PTSD), pose significant challenges to global mental health. While the etiology of these disorders involves a complex interplay of genetic, environmental, and psychosocial factors, emerging evidence suggests a pivotal role of epigenetic modifications in their pathogenesis. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation, dynamically regulate gene expression in response to stressors, thereby influencing brain function and behaviour. Alterations in these epigenetic processes contribute to aberrant stress responses, increased susceptibility to stress-related disorders, and individual differences in stress vulnerability and resilience. Moreover, epigenetic modifications can be transmitted across generations, highlighting the enduring impact of stress on mental health outcomes. Understanding the mechanisms underlying epigenetic regulation in stress-related disorders provides insights into disease pathogenesis and potential biomarkers for diagnosis and prognosis. Additionally, targeting epigenetic pathways represents a promising therapeutic approach for these disorders. Epigenetic drugs, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors, hold potential for mitigating the adverse effects of stress on mental health. However, challenges such as off-target effects and lack of specificity necessitate further refinement of epigenetic-based therapies.

Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy

Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.

Research progress of non-coding RNA-mediated regulation of the osteogenesis of periodontal tissues when mechanical tension is applied

Research progress of non-coding RNA-mediated regulation of the osteogenesis of periodontal tissues when mechanical tension is applied

Long noncoding RNA-mediated epigenetic regulation of auxin-related genes controls shade avoidance syndrome in Arabidopsis.

The long noncoding RNA (lncRNA) AUXIN-REGULATED PROMOTER LOOP (APOLO) recognizes a subset of target loci across the Arabidopsis thaliana genome by forming RNA-DNA hybrids (R-loops) and modulating local three-dimensional chromatin conformation. Here, we show that APOLO regulates shade avoidance syndrome by dynamically modulating expression of key factors. In response to far-red (FR) light, expression of APOLO anti-correlates with that of its target BRANCHED1 (BRC1), a master regulator of shoot branching in Arabidopsis thaliana. APOLO deregulation results in BRC1 transcriptional repression and an increase in the number of branches. Accumulation of APOLO transcription fine-tunes the formation of a repressive chromatin loop encompassing the BRC1 promoter, which normally occurs only in leaves and in a late response to far-red light treatment in axillary buds. In addition, our data reveal that APOLO participates in leaf hyponasty, in agreement with its previously reported role in the control of auxin homeostasis through direct modulation of auxin synthesis gene YUCCA2, and auxin efflux genes PID and WAG2. We show that direct application of APOLO RNA to leaves results in a rapid increase in auxin signaling that is associated with changes in the plant response to far-red light. Collectively, our data support the view that lncRNAs coordinate shade avoidance syndrome in A. thaliana, and reveal their potential as exogenous bioactive molecules. Deploying exogenous RNAs that modulate plant-environment interactions may therefore become a new tool for sustainable agriculture.

Transcriptional Analysis of lncRNA and Target Genes Induced by Influenza A Virus Infection in MDCK Cells.

The MDCK cell line is the primary cell line used for influenza vaccine production. Using genetic engineering technology to change the expression and activity of genes that regulate virus proliferation to obtain high-yield vaccine cell lines has attracted increasing attention. A comprehensive understanding of the key genes, targets, and molecular mechanisms of viral regulation in cells is critical to achieving this goal, yet the post-transcriptional regulation mechanism involved in virus proliferation-particularly the effect of lncRNA on influenza virus proliferation-is still poorly understood. Therefore, this study used high-throughput RNA-seq technology to identify H1N1 infection-induced lncRNA and mRNA expression changes in MDCK cells and explore the regulatory relationship between these crucial lncRNAs and their target genes. In response to H1N1 infection in MDCK cells 16 h post-infection (hpi) relative to uninfected controls, we used multiple gene function annotation databases and initially identified 31,501 significantly differentially expressed (DE) genes and 39,920 DE lncRNAs (|log2FC| > 1, p < 0.05). Among these, 102 lncRNAs and 577 mRNAs exhibited predicted correlations with viral response mechanisms. Based on the magnitude of significant expression differences, related research, and RT-qPCR expression validation at the transcriptional level, we further focused on 18 DE mRNAs and 32 DE lncRNAs. Among these, the differential expression of the genes RSAD2, CLDN1, HCLS1, and IFIT5 in response to influenza virus infection was further verified at the protein level using Western blot technology, which showed results consistent with the RNA-seq and RT-qPCR findings. We then developed a potential molecular regulatory network between these four genes and their six predicted lncRNAs. The results of this study will contribute to a more comprehensive understanding of the molecular mechanism of host cell non-coding RNA-mediated regulation of influenza virus replication. These results may also identify methods for screening target genes in the development of genetically engineered cell lines capable of high-yield artificial vaccine production.

Amplifying gene expression with RNA-targeted therapeutics.

Many diseases are caused by insufficient expression of mutated genes and would benefit from increased expression of the corresponding protein. However, in drug development, it has been historically easier to develop drugs with inhibitory or antagonistic effects. Protein replacement and gene therapy can achieve the goal of increased protein expression but have limitations. Recent discoveries of the extensive regulatory networks formed by non-coding RNAs offer alternative targets and strategies to amplify the production of a specific protein. In addition to RNA-targeting small molecules, new nucleic acid-based therapeutic modalities that allow highly specific modulation of RNA-based regulatory networks are being developed. Such approaches can directly target the stability of mRNAs or modulate non-coding RNA-mediated regulation of transcription and translation. This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

Myeloid-derived suppressor cell: A crucial player in autoimmune diseases.

Myeloid-derived suppressor cells (MDSCs) are identified as a highly heterogeneous group of immature cells derived from bone marrow and play critical immunosuppressive functions in autoimmune diseases. Accumulating evidence indicates that the pathophysiology of autoimmune diseases was closely related to genetic mutations and epigenetic modifications, with the latter more common. Epigenetic modifications, which involve DNA methylation, covalent histone modification, and non-coding RNA-mediated regulation, refer to inheritable and potentially reversible changes in DNA and chromatin that regulate gene expression without altering the DNA sequence. Recently, numerous reports have shown that epigenetic modifications in MDSCs play important roles in the differentiation and development of MDSCs and their suppressive functions. The molecular mechanisms of differentiation and development of MDSCs and their regulatory roles in the initiation and progression of autoimmune diseases have been extensively studied, but the exact function of MDSCs remains controversial. Therefore, the biological and epigenetic regulation of MDSCs in autoimmune diseases still needs to be further characterized. This review provides a detailed summary of the current research on the regulatory roles of DNA methylation, histone modifications, and non-coding RNAs in the development and immunosuppressive activity of MDSCs, and further summarizes the distinct role of MDSCs in the pathogenesis of autoimmune diseases, in order to provide help for the diagnosis and treatment of diseases from the perspective of epigenetic regulation of MDSCs.

Noncoding RNA-mediated regulation of pyroptotic cell death in cancer.

Pyroptosis is a newly discovered form of programmed cell death, which is manifested by DNA fragmentation, cell swelling, cell membrane rupture and leakage of cell contents. Previous studies have demonstrated that pyroptosis is tightly associated with the initiation and development of various cancers, whereas the molecular mechanisms underlying pyroptosis remain obscure. Noncoding RNAs (ncRNAs) are a type of heterogeneous transcripts that are broadly expressed in mammalian cells. Owing to their potency of regulating gene expression, ncRNAs play essential roles in physiological and pathological processes. NcRNAs are increasingly acknowledged as important regulators of the pyroptosis process. Importantly, the crosstalk between ncRNAs and pyroptosis affects various hallmarks of cancer, including cell growth, survival, metastasis and therapeutic resistance. The study of the involvement of pyroptosis-associated ncRNAs in cancer pathobiology has become a hot area in recent years, while there are limited reviews on this topic. Herein, we provide an overview of the complicated roles of ncRNAs, mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in modulating pyroptosis, with a focus on the underlying mechanisms of the ncRNA-pyroptosis axis in cancer pathogenesis. Finally, we discuss the potential applications and challenges of exploiting pyroptosis-regulating ncRNAs as molecular biomarkers and therapeutic targets in cancer.

Unraveling the Epigenetic Landscape for Salt Tolerance in Plants

In every organism, the expression of genes is regulated in response to the changes in the surrounding environment. The study of epigenetics in plants is essential in view of the improvement of agricultural productivity. Epigenetic modifications can enhance crops’ yield and stress tolerance without making any alteration within their genomic sequences. The routes of epigenetic modifications include processes such as methylation of DNA, modifications of histone proteins, chromatin remodeling, and non-coding RNA-mediated regulation of genes. Genome-wide epigenetic profiles, coined as the epigenome, of several plants have been identified in recent years. In the scope of this review, we are going to discuss progress made in the field of plant epigenomics under the limelight of stress tolerance, especially saline conditions.

Implication of non-coding RNA-mediated ROCK1 regulation in various diseases.

Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) is a protein serine/threonine kinase which is activated upon binding with the GTP-bound form of Rho. This protein can modulate actin-myosin contraction and stability. Moreover, it has a crucial role in the regulation of cell polarity. Therefore, it participates in modulation of cell morphology, regulation of expression of genes, cell proliferation and differentiation, apoptotic processes as well as oncogenic processes. Recent studies have highlighted interactions between ROCK1 and several non-coding RNAs, namely microRNAs, circular RNAs and long non-coding RNAs. Such interactions can be a target of medications. In fact, it seems that the interactions are implicated in therapeutic response to several medications. In the current review, we aimed to explain the impact of these interactions in the pathoetiology of cancers as well as non-malignant disorders.

Recent insights into the microRNA and long non-coding RNA-mediated regulation of stem cell populations.

Stem cells are undifferentiated cells that have multi-lineage differentiation. The transition from self-renewal to differentiation requires rapid and extensive gene expression alterations. Since different stem cells exhibit diverse non-coding RNAs (ncRNAs) expression profiles, the critical roles of ncRNAs in stem cell reprogramming, pluripotency maintenance, and differentiation have been widely investigated over the past few years. Hence, in this current review, the two main categories of ncRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are discussed. While the primary way by which miRNAs restrict mRNA transcription is through miRNA-mRNA interaction, lncRNAs have a wide range of effects on mRNA functioning, including interactions with miRNAs. Both of these ncRNAs participate in the post-transcriptional regulation of crucial biological mechanisms, such as cell cycle regulation, apoptosis, aging, and cell fate decisions. These findings shed light on a previously unknown aspect of gene regulation in stem cell fate determination and behavior. Overall, we summarized the key roles of miRNAs (including exosomal miRNAs) and lncRNAs in the regulation of stem cell populations, such as cardiac, hematopoietic, mesenchymal, neural, and spermatogonial, as well ncRNAs' influence on malignancy through modulating cancer stem cells, which might significantly contribute to clinical stem cell therapy and in regenerative medicine.

In Vivo Reductionist Approach Identifies miR-15a Protecting Mice From Obesity.

Obesity is a growing medical and social problem worldwide. The control of energy homeostasis in the brain is achieved by various regions including the arcuate hypothalamic nucleus (ARH). The latter comprises a number of neuronal populations including the first order metabolic neurons, appetite-stimulating agouti-related peptide (AgRP) neurons and appetite-suppressing proopiomelanocortin (POMC) neurons. Using an in vivo reductionist approach and POMCCre-dependent CRISPR-Cas9, we demonstrate that miR-15a-5p protects from obesity. Moreover, we have identified Bace1, a gene previously linked to energy metabolism imbalance, as a direct target of miR-15a-5p. This work warrants further investigations of non-coding RNA-mediated regulation of energy homeostasis and might contribute to the development of novel therapeutic approaches to treat metabolic diseases.

Association of polymorphisms in four low-penetrance genes (ACYP2, CCNE1, ERCC5 and lincRNA CASC22) with breast cancer risk in a Vietnamese population

In breast cancer (BC), four low-penetrance genes (ACYP2, CCNE1, ERCC5 and lincRNA CASC22) are involved in cell cycle arrest, DNA damage repair and long non-coding RNA-mediated regulation is commonly known as causative genes of tumorigenesis. A functional polymorphism in these genes may cause cancer by altering the genes' structure and function. Single Nucleotide Polymorphisms (SNPs) have been discovered to be capable of predicting cancer risk, hence can be used as carcinogenesis markers. To date, the correlation of four SNPs (rs12621038, rs3218038, rs751402 and rs12325489) with BC risk in different populations has been revealed by numerous researches. This study examines the association between these SNPs and the risk of developing BC in Vietnamese women. These four SNPs were genotyped by HRM assay. The differences in allelic and genotypic frequencies between cases and controls were analyzed to determine their relationship with BC risk. While rs12621038, rs3218038 and rs751402 showed no relation to BC, there was an association between rs12325489 and BC risk. In both codominant and overdominant models, the lincRNA CASC22 rs12325489 was consistently associated with BC risk (TT vs. CC: OR = 0.63, 95% CI = 0.44 to 0.90, P = 0.01 and TC vs. TT + CC: OR = 0.61, 95% CI = 0.43 to 0.84, P = 0.003; respectively). These results indicated that rs12325489 could be a potential biomarker for predicting BC risk in Vietnamese women.

Epigenetic Modifications in Tumor-Associated Macrophages: A New Perspective for an Old Foe.

Tumorigenesis is frequently accompanied by chronic inflammation, and the tumor microenvironment (TME) can be considered an ecosystem that consists of tumor cells, endotheliocytes, fibroblasts, immune cells and acellular components such as extracellular matrix. For tumor cells, their survival advantages are dependent on both genetic and epigenetic alterations, while other cells mainly present epigenetic modifications. Macrophages are the most plastic type of immune cells and undergo diverse epigenetic alterations in the TME. Some of these epigenetic modifications mitigate against cancer progression, and others accelerate this process. Due to the complex roles of macrophages in the TME, it is urgent to understand their epigenetic modifications associated with the TME. Here, we mainly summarize recent findings on TME-associated epigenetic alterations of tumor-associated macrophages (TAMs), including DNA methylation, posttranslational modifications of histone proteins, chromatin remodeling, and noncoding RNA-mediated epigenetic regulation. At the end of this review, we also discuss the translational potential of these epigenetic modifications for developing novel cancer therapies targeting TAMs.

Long Noncoding RNA Mediated Regulation in Human Embryogenesis, Pluripotency, and Reproduction.

Long noncoding RNAs (lncRNAs), a class of noncoding RNAs with more than 200 bp in length, are produced by pervasive transcription in mammalian genomes and regulate gene expression through various action mechanisms. Accumulating data indicate that lncRNAs mediate essential biological functions in human development, including early embryogenesis, induction of pluripotency, and germ cell development. Comprehensive analysis of sequencing data highlights that lncRNAs are expressed in a stage-specific and human/primate-specific pattern during early human development. They contribute to cell fate determination through interacting with almost all classes of cellular biomolecules, including proteins, DNA, mRNAs, and microRNAs. Furthermore, the expression of a few of lncRNAs is highly associated with the pathogenesis and progression of many reproductive diseases, suggesting that they could serve as candidate biomarkers for diagnosis or novel targets for treatment. Here, we review research on lncRNAs and their roles in embryogenesis, pluripotency, and reproduction. We aim to identify the underlying molecular mechanisms essential for human development and provide novel insight into the causes and treatments of human reproductive diseases.

Epigenetic regulation of ion channels in the sense of taste

There are five fundamental tastes discovered so far: sweet, bitter, umami, sour and salty. Taste is mediated by the specialized neuroepithelial cells mainly located at the tongue papillae, namely taste receptor cells, which can be classified into type I, type II, type III and type IV. Ion channels are necessary for diverse cell physiological activities including taste sensing, smell experience and temperature perception. Existing evidences have demonstrated distinct structures and working models of ion channels. Epigenetic modifications regulate gene expression mainly through histone modifications, DNA methylation and non-coding RNA-mediated regulation, without altering DNA sequence. This review summarizes how ion channels work during the transduction of multiple tastes, as well as the recent progressions in the epigenetic regulation of ion channels.

Role of Epigenetic Regulation in Plasticity of Tumor Immune Microenvironment.

The tumor immune microenvironment (TIME), an immunosuppressive niche, plays a pivotal role in contributing to the development, progression, and immune escape of various types of cancer. Compelling evidence highlights the feasibility of cancer therapy targeting the plasticity of TIME as a strategy to retrain the immunosuppressive immune cells, including innate immune cells and T cells. Epigenetic alterations, such as DNA methylation, histone post-translational modifications, and noncoding RNA-mediated regulation, regulate the expression of many human genes and have been reported to be accurate in the reprogramming of TIME according to vast majority of published results. Recently, mounting evidence has shown that the gut microbiome can also influence the colorectal cancer and even extraintestinal tumors via metabolites or microbiota-derived molecules. A tumor is a kind of heterogeneous disease with specificity in time and space, which is not only dependent on genetic regulation, but also regulated by epigenetics. This review summarizes the reprogramming of immune cells by epigenetic modifications in TIME and surveys the recent progress in epigenetic-based cancer clinical therapeutic approaches. We also discuss the ongoing studies and future areas of research that benefits to cancer eradication.

Epigenetic Regulation of Gibberellin Metabolism and Signaling.

The precise regulation of gibberellin (GA) metabolism and signaling is essential for plant development and environmental responses. Epigenetic regulatory mechanisms, such as histone modification, noncoding RNA-mediated regulation, chromatin remodeling and DNA methylation, are emerging as important means of fine-tuning gene expression. Recent studies have significantly improved our understanding of the relationships between epigenetic regulation and GA metabolism and signaling. Here, we summarize the molecular mechanisms by which epigenetic modifications affect GA metabolism and signaling pathways and provide new insight into an unfolding avenue of research related to the epigenetic regulation of GA pathways.

The Functions of Non-coding RNAs in rRNA Regulation.

Ribosomes are ribonucleoprotein machines that decode the genetic information embedded in mRNAs into polypeptides. Ribosome biogenesis is tightly coordinated and controlled from the transcription of pre-rRNAs to the assembly of ribosomes. Defects or disorders in rRNA production result in a number of human ribosomopathy diseases. During the processes of rRNA synthesis, non-coding RNAs, especially snoRNAs, play important roles in pre-rRNA transcription, processing, and maturation. Recent research has started to reveal that other long and short non-coding RNAs, including risiRNA, LoNA, and SLERT (among others), are also involved in pre-rRNA transcription and rRNA production. Here, we summarize the current understanding of the mechanisms of non-coding RNA-mediated rRNA generation and regulation and their biological roles.

Long Non-Coding RNA-Mediated Regulation of the Interferon Response: A New Perspective on a Familiar Theme

The interferon (IFN) response is a critical and ubiquitous component of the innate immune response to pathogens. Detailed studies in the last decades have elucidated the function of a large number of proteins that mediate the complex signaling pathways and gene expression programs involved in the interferon response. The recent discovery of the long non-coding RNAs (lncRNAs) as a new category of cellular effectors has led to studies aiming to understand the role of these transcripts in the IFN response. Several high throughput studies have shown that a large number of lncRNAs are differentially expressed following IFN stimulation and/or viral infections. In-depth study of a very small fraction of the identified lncRNAs has revealed critical roles for this class of transcripts in the regulation of multiple steps of the IFN response, and pointed to the presence of an extensive RNA-mediated regulatory network during the antiviral response. As the vast majority of the identified potential regulatory lncRNAs remain unstudied, it is highly likely that future studies will reveal a completely new perspective on the regulation of the IFN response, with lncRNA- and protein-mediated regulatory networks coordinating the duration, magnitude, and character of this aspect of the innate immune response. In addition to providing a more complete picture of the IFN response, these studies will likely identify new therapeutic targets that in the long term may impact the therapeutic options available against microbial infections and diseases of the immune system.