Regulation of m6A (N6-Methyladenosine) methylation modifiers in solid cancers.

Solid cancers constitute a tremendous burden on global healthcare, requiring a deeper understanding of the molecular mechanisms underlying cancer development and progression. Epigenetic changes, notably N6-methyladenosine (m6A) RNA methylation, have emerged as important contributors to the biology of solid tumors in recent years. This epigenetic mark dynamically affects gene expression at the post-transcriptional level and modulates a variety of cellular processes, making it a focus of research in the context of solid tumors. m6A modification patterns are dysregulated in a variety of solid cancers, including ovarian, breast, lung, colorectal, pancreatic, and others. This dysregulated m6A landscape has been shown to induce significant changes in the expression of oncogenes, tumor suppressors, and genes involved in cancer stem cells, metastasis, and treatment resistance. In solid tumors, the interaction of m6A "writers" (e.g., METTL3, METTL14, and others), "erasers" (e.g., ALKBH5, FTO), and "readers" (e.g., members of YTHDF proteins and others) delicately changes the m6A methylome. Targeting m6A regulators as a potential therapeutic method to control gene expression and prevent tumor development seems a novel strategy. To enhance treatment results, advances in this area of research have led to the development of targeted treatments aiming at restoring or altering m6A alteration patterns in solid tumors.

Single-cell transcriptomics reveals writers of RNA modification-mediated immune microenvironment and cardiac resident Macro-MYL2 macrophages in heart failure.

BACKGROUND: Heart failure (HF), which is caused by cardiac overload and injury, is linked to significant mortality. Writers of RNA modification (WRMs) play a crucial role in the regulation of epigenetic processes involved in immune response and cardiovascular disease. However, the potential roles of these writers in the immunological milieu of HF remain unknown. METHODS: We comprehensively characterized the expressions of 28 WRMs using datasets GSE145154 and GSE141910 to map the cardiac immunological microenvironment in HF patients. Based on the expression of WRMs, the immunological cells in the datasets were scored. RESULTS: Single-cell transcriptomics analysis (GSE145154) revealed immunological dysregulation in HF as well as differential expression of WRMs in immunological cells from HF and non-HF (NHF) samples. WRM-scored immunological cells were positively correlated with the immunological response, and the high WRM score group exhibited elevated immunological cell infiltration. WRMs are involved in the differentiation of T cells and myeloid cells. WRM scores of T cell and myeloid cell subtypes were significantly reduced in the HF group compared to the NHF group. We identified a myogenesis-related resident macrophage population in the heart, Macro-MYL2, that was characterized by an increased expression of cardiomyocyte structural genes (MYL2, TNNI3, TNNC1, TCAP, and TNNT2) and was regulated by TRMT10C. Based on the WRM expression pattern, the transcriptomics data (GSE141910) identified two distinct clusters of HF samples, each with distinct functional enrichments and immunological characteristics. CONCLUSION: Our study demonstrated a significant relationship between the WRMs and immunological microenvironment in HF, as well as a novel resident macrophage population, Macro-MYL2, characterized by myogenesis. These results provide a novel perspective on the underlying mechanisms and therapeutic targets for HF. Further experiments are required to validate the regulation of WRMs and Macro-MYL2 macrophage subtype in the cardiac immunological milieu.

Comparative Transcriptomics to Identify RNA Writers and Erasers in Microalgae.

Epitranscriptomics is considered as a new regulatory step in eukaryotes for developmental processes and stress responses. The aim of this study was, for the first time, to identify RNA methyltransferase (writers) and demethylase (erasers) in four investigated species, i.e., the dinoflagellates Alexandrium tamutum and Amphidinium carterae, the diatom Cylindrotheca closterium, and the green alga Tetraselmis suecica. As query sequences for the enzymatic classes of interest, we selected those ones that were previously detected in marine plants, evaluating their expression upon nutrient starvation stress exposure. The hypothesis was that upon stress exposure, the activation/deactivation of specific writers and erasers may occur. In microalgae, we found almost all plant writers and erasers (ALKBH9B, ALKBH10B, MTB, and FIP37), except for three writers (MTA, VIRILIZER, and HAKAI). A sequence similarity search by scanning the corresponding genomes confirmed their presence. Thus, we concluded that the three writer sequences were lacking from the studied transcriptomes probably because they were not expressed in those experimental conditions, rather than a real lack of these genes from their genomes. This study showed that some of them were expressed only in specific culturing conditions. We also investigated their expression in other culturing conditions (i.e., nitrogen depletion, phosphate depletion, and Zinc addition at two different concentrations) in A. carterae, giving new insights into their possible roles in regulating gene expression upon stress.

Work Environment and Depressive Symptoms of Webtoon Writers.

Background: Webtoon, a digital form of comics created in the Republic of Korea, has spread widely with advantages that anyone can become a cartoonist and that autonomy of creation is guaranteed. The purpose of this study is to identify the working conditions of webtoon writers and analyze the relationship between these conditions and depressive symptoms. Methods: A survey was carried out on webtoon writers and a survey data of 312 webtoon writers were analyzed. The questionnaire included basic socio-demographic characteristics, webtoon writers' contractual type, fields of activity (webtoon creator, story writer, illustrator), and working environment (labor discretion etc.). We investigated depressive symptoms and analyzed its relation to the work environment of webtoon writers. Results: Webtoon writers were exposed to long working hours, high labor intensity, limited labor discretion, negative comments from readers, and had a high prevalence of depressive symptoms. Compared to story writers who contracted directly with platforms, story writers and the illustrators who contracted with content providers (CPs) were 9.51 times (OR = 9.51, 95% CI = 1.47 - 61.33) and 6.47 times (OR = 6.47, 95% CI = 1.08 - 38.75) more likely to have depressive symptoms, respectively. Conclusions: This study emphasizes the urgent necessity to improve the overall working environment in the webtoon industry and implement measures to tackle the escalating mental health challenges faced by illustrators and story writers contracted with CPs, especially given the increasing popularity of novel comics.

Regulations of m6A and other RNA modifications and their roles in cancer.

RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N6,2'-O-dimethyladenosine (m6Am), N4-acetylcytidine (ac4C), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially m6A) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.

Research progress of N1-methyladenosine RNA modification in cancer.

N1-methyladenosine (m1A) is a post-transcriptionally modified RNA molecule that plays a pivotal role in the regulation of various biological functions and activities. Especially in cancer cell invasion, proliferation and cell cycle regulation. Over recent years, there has been a burgeoning interest in investigating the m1A modification of RNA. Most studies have focused on the regulation of m1A in cancer enrichment areas and different regions. This review provides a comprehensive overview of the methodologies employed for the detection of m1A modification. Furthermore, this review delves into the key players in m1A modification, known as the "writers," "erasers," and "readers." m1A modification is modified by the m1A methyltransferases, or writers, such as TRMT6, TRMT61A, TRMT61B, TRMT10C, NML, and, removed by the demethylases, or erasers, including FTO and ALKBH1, ALKBH3. It is recognized by m1A-binding proteins YTHDF1, TYHDF2, TYHDF3, and TYHDC1, also known as "readers". Additionally, we explore the intricate relationship between m1A modification and its regulators and their implications for the development and progression of specific types of cancer, we discuss how m1A modification can potentially facilitate the discovery of novel approaches for cancer diagnosis, treatment, and prognosis. Our summary of m1A methylated adenosine modification detection methods and regulatory mechanisms in various cancers provides useful insights for cancer diagnosis, treatment, and prognosis. Video Abstract.

Primary School Teachers' Adaptations for Struggling Writers: Survey Study of Grade 1 to 6 Teachers in Australia.

Two hundred ninety-eight primary teachers (88% female) from across all Australian states and territories reported on the frequency with which they implemented instructional adaptations for struggling writers in their classrooms. They also rated their preparation and self-efficacy for teaching writing. The majority of participating teachers indicated they provided additional instruction on spelling, capitalization and punctuation, and sentence construction at least once a week or more often. Teachers further reported implementing additional minilessons and reteaching strategies and skills, as well as extra instruction on grammar, handwriting, text structure, revising, and planning on a monthly basis or more often. The majority of teachers reported never or only once a year using adaptations to support digital writing. The frequency with which teachers provided extra instruction on spelling, handwriting, text structure, revising, and computer use differed by grade. Only teachers' perceived efficacy to teach writing made a unique and statistically significant contribution to predicting the use of instructional adaptations for writing and adaptations to support digital writing after controlling for teacher and classroom variables.

The impact of a changed writing environment on students' motivation to write.

Introduction: The act of writing is widely acknowledged to be a complex and challenging activity, and in parallel, we know that student motivation to write is a predictor of writing performance. So understanding what characteristics of the writing classroom support or foster motivation remains a salient concern. Research has shown that UK teachers are more likely to see themselves as readers than writers, which may affect how they teach writing. Methods: This paper reports on student focus group interview data from a study which sought to strengthen teachers' sense of themselves as writers, and to examine the impact of this on students' classroom experience of writing and their writing outcomes. The participant teachers experienced a creative writing residential, which established a writing community led by two professional writers, with the goal of changing teachers' professional practice in their own writing classrooms. The study was mixed methods, comprising a randomized controlled trial and a comprehensive qualitative dataset collating data from both the residential and the classroom. This paper presents the qualitative analysis of 32 interviews with 16 student focus groups, exploring their responses to their teachers' changed practices and how it connected with their motivation to write. Results: The interview analysis shows how many students responded positively to new teaching practices which gave them greater autonomy and choice, and established a more collaborative way of working. This led to increased confidence in and motivation to write. Discussion: The study highlights the importance of the classroom environment in supporting and sustaining motivation to write, and underlines that motivation is not simply an internal characteristic of an individual but is situated within the context of a community of writers.

Emerging roles of biological m6A proteins in regulating virus infection: A review.

N6-methyladenosine (m6A) is the most prevalent chemical modifications of intracellular RNA, which recently emerging as a multifaceted effector of viral genomic RNA. As a dynamic process, three groups of biological proteins control the levels of m6A modification in eukaryocyte, designed as m6A writers, erasers, and readers. The m6A writers comprising of methyltransferases complex initiate the modification process. On the contrary, the m6A erasers ALKBH5 or FTO abolish the modification through three-step demethylation: m6A to N6-hydroxymethyl adenosine (hm6A), then hm6A to N6-methyladenosine (f6A), and finally f6A to adenosine. The known m6A readers include the YTH family and the hnRNP family. As m6A modification regulates RNA nuclear exportation, stability, and translation, m6A proteins commonly participate in virus infection by regulating viral genomic RNA synthesis. Moreover, m6A proteins establish molecular linkages between virus genome/viral encode proteins and host cells proteins via their multifunctional roles in cellular RNA metabolism. The m6A writers and erasers directly impact interferon expression and macrophage innate immune responses, facilitating them to act as anti-/pro-viral factors. The m6A readers enable to alter cell metabolism and stress granules (SGs) production to regulate virus-host interactions. Here, the latest progress of m6A proteins in regulating viral infection is reviewed. Demonstrating the roles of m6A proteins will enhance the understanding of epigenetic regulation of virus infection and stimulate the development of novel antiviral strategies.

The implications of N6-methyladenosine (m6A) modification in esophageal carcinoma.

Esophageal carcinoma (EC) is always diagnosed at advanced stage and its the mortality rate remains high. The patients usually miss the best opportunity for treatment because of non-specific symptoms and the survival rates are low. N6-methyladenosine (m6A) the predominant modification in eukaryotic messenger RNA(mRNA), serves vital roles in numerous bioprocess. This chemical modification is dynamic, reversible and consists of three regulators: m6A methyltransferases (writers), demethylases (erasers) and m6A-binding proteins (readers). Recently, a growing number of evidences have indicated relationships between m6A and EC. Whereas, lacking of cognition about the molecular mechanism of m6A modification in esophageal carcinoma. We will focus on the biological function roles of m6A modification in the tumorigenesis and development of EC. Recent studies showed that immunotherapy had a positive impact on EC. The relationship between m6A and immunotherapy in EC deserves further research and discussion. We will also discuss the potential clinical applications regarding diagnosis, treatment and prognosis of m6A modification for EC and provide perspectives for further studies.

Four types of adenine-related RNA modification writers -mediated molecular subtypes contribute to predicting clinical outcomes and treatment options in bladder cancer.

Rationale: RNA modifications, containing m6A, m1A, alternative polyadenylation and adenosine-to-inosine RNA editing, involve in critical cancerous immunity and cancerous processes. However, the functional roles of RNA modification writers in bladder cancer (BLCA) are largely unknown. Methods: In this study, unsupervised clustering was used to identify novel RNA modification writers -mediated molecular subtypes in BLCA. A corresponding quantitative indicator called WriterScore was developed using univariate Cox and Least absolute shrinkage and selection operator (LASSO) analysis. Then, we systematically analyzed the correlation between RNA modification writer-related clusters (WriterScore) and immunological characteristics, classical molecular subtypes, clinicopathologic features and treatment options in BLCA. Finally, we validated the WriterScore in multiple other external BLCA datasets, clinical sample dataset in Shengjing Hospital and pancancer. Results: Two RNA modification writer-related clusters and three DEGclusters were obtained. These RNA modification writer-related clusters (WriterScore) were strongly associated with immunological characteristics, classical molecular subtypes, clinicopathologic features of BLCA. Moreover, WriterScore can properly predict the clinical outcomes and immunotherapy of BLCA patients. Conclusion: Our study systematically investigated the role of RNA modification writers and developed a significant WriterScore to guide several treatment options in BLCA, which might bring some potential benefits for BLCA patients.

The self-reflexivity in transnational literature: Re-writing the migration in female migrant writers.

The main aim of this paper is to discuss the socio-political meaning of the transnational literary production made by female migrant writers. Thus, it analyses their role in the framework of the 'hybrid' literary production of the 21st century in Europe, such as Spain and Italy. Moving away from the idea of national literatures, this paper investigates literature as a geographical and emotional inquiry point and friction between languages, ideas, practices, literary institutions, female authors, and female voices in today's markets. Hybrid literature written by first and second-generation migrants and displaced people is part of a huger concept of transnational literature, which breaks down with the idea of national identity and transiting towards a new conceptualization of hybridity in the literary production, also based on the translation of writings to other languages. The research question is about the relation between the transnational literary works, written by migrant women, and the social change. Based on the conceptualization of the Bhabha's 'third space', I will analyse the relation between the positioning of female migrant writers of 21st century and the role of hybridity. The preliminary findings show, firstly, the idea of reconceptualising it appears in light of the complexity of migrant people's realities and sex-gender differences. By adopting an intersectional lens, focused on the dialectic between gender and race/ethnicity and class, this paper analyses the tensions embedded in the re-positioning of four female migrant writers and their transnational experience (self)reflected in their writings. The present research contributes to the scientific knowledge in the field of cross-cultural literary studies, crossed with the migration study, through questioning the changing gender role and relations in transnational migrant literature. In addition, the findings show that today's reflection on 'third space' theory in the diasporic literature seems an idea to be refined when migrant women are involved.

Disruption of the mouse liver epitranscriptome by long-term aroclor 1260 exposure.

Chronic environmental exposure to polychlorinated biphenyls (PCBs) is associated with non-alcoholic fatty liver disease (NAFLD) and exacerbated by a high fat diet (HFD). Here, chronic (34 wks.) exposure of low fat diet (LFD)-fed male mice to Aroclor 1260 (Ar1260), a non-dioxin-like (NDL) mixture of PCBs, resulted in steatohepatitis and NAFLD. Twelve hepatic RNA modifications were altered with Ar1260 exposure including reduced abundance of 2'-O-methyladenosine (Am) and N(6)-methyladenosine (m6A), in contrast to increased Am in the livers of HFD-fed, Ar1260-exposed mice reported previously. Differences in 13 RNA modifications between LFD- and HFD- fed mice, suggest that diet regulates the liver epitranscriptome. Integrated network analysis of epitranscriptomic modifications identified a NRF2 (Nfe2l2) pathway in the chronic, LFD, Ar1260-exposed livers and an NFATC4 (Nfatc4) pathway for LFD- vs. HFD-fed mice. Changes in protein abundance were validated. The results demonstrate that diet and Ar1260 exposure alter the liver epitranscriptome in pathways associated with NAFLD.

An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability.

In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the cis H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with cis H3K4 methylation levels. Together, these observations reveal an acetylation 'chromatin switch' on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.

Prolific non-research authors in high impact scientific journals: meta-research study.

Journalistic papers published in high impact scientific journals can be very influential, especially in hot fields. This meta-research analysis aimed to evaluate the publication profiles, impact, and disclosures of conflicts of interest of non-research authors who had published > 200 Scopus-indexed papers in Nature, Science, PNAS, Cell, BMJ, Lancet, JAMA or New England Journal of Medicine. 154 prolific authors were identified, 148 of whom had published 67,825 papers in their main affiliated journal in a non-researcher capacity. Nature, Science, and BMJ have the lion's share of such authors. Scopus characterized 35% of the journalistic publications as full articles and another 11% as short surveys. 264 papers had received more than 100 citations. 40/41 most-cited papers in 2020-2022 were on hot COVID-19 topics. Of 25 massively prolific authors with > 700 publications in one of these journals, many were highly-cited (median citations 2273), almost all had published little or nothing in the Scopus-indexed literature other than in their main affiliated journal, and their influential writing covered diverse hot topics over the years. Of the 25, only 3 had a PhD degree in any subject matter, and 7 had a Master's degree in journalism. Only the BMJ offered conflicts of interest disclosures for prolific science writers in its website, but even then only 2 of the 25 massively prolific authors disclosed potential conflicts with some specificity. The practice of assigning so much power to non-researchers in shaping scientific discourse should be further debated and disclosures of potential conflicts of interest should be emphasized.

RNA methylation in plants: An overview.

RNA methylation is an important post-transcriptional modification that influences gene regulation. Over 200 different types of RNA modifications have been identified in plants. In animals, the mystery of RNA methylation has been revealed, and its biological role and applications have become increasingly clear. However, RNA methylation in plants is still poorly understood. Recently, plant science research on RNA methylation has advanced rapidly, and it has become clear that RNA methylation plays a critical role in plant development. This review summarizes current knowledge on RNA methylation in plant development. Plant writers, erasers, and readers are highlighted, as well as the occurrence, methods, and software development in RNA methylation is summarized. The most common and abundant RNA methylation in plants is N6-methyladenosine (m6A). In Arabidopsis, mutations in writers, erasers, and RNA methylation readers have affected the plant's phenotype. It has also been demonstrated that methylated TRANSLATIONALLY CONTROLLED TUMOR PROTEIN 1-messenger RNA moves from shoot to root while unmethylated TCTP1-mRNA does not. Methylated RNA immunoprecipitation, in conjunction with next-generation sequencing, has been a watershed moment in plant RNA methylation research. This method has been used successfully in rice, Arabidopsis, Brassica, and maize to study transcriptome-wide RNA methylation. Various software or tools have been used to detect methylated RNAs at the whole transcriptome level; the majority are model-based analysis tools (for example, MACS2). Finally, the limitations and future prospects of methylation of RNA research have been documented.

The Repertoire of RNA Modifications Orchestrates a Plethora of Cellular Responses.

Although a plethora of DNA modifications have been extensively investigated in the last decade, recent breakthroughs in molecular biology, including high throughput sequencing techniques, have enabled the identification of post-transcriptional marks that decorate RNAs; hence, epitranscriptomics has arisen. This recent scientific field aims to decode the regulatory layer of the transcriptome and set the ground for the detection of modifications in ribose nucleotides. Until now, more than 170 RNA modifications have been reported in diverse types of RNA that contribute to various biological processes, such as RNA biogenesis, stability, and transcriptional and translational accuracy. However, dysfunctions in the RNA-modifying enzymes that regulate their dynamic level can lead to human diseases and cancer. The present review aims to highlight the epitranscriptomic landscape in human RNAs and match the catalytic proteins with the deposition or deletion of a specific mark. In the current review, the most abundant RNA modifications, such as N6-methyladenosine (m6A), N5-methylcytosine (m5C), pseudouridine (Ψ) and inosine (I), are thoroughly described, their functional and regulatory roles are discussed and their contributions to cellular homeostasis are stated. Ultimately, the involvement of the RNA modifications and their writers, erasers, and readers in human diseases and cancer is also discussed.

Application of CRISPR Cas systems in DNA recorders and writers.

The necessity to record and store biological data is increasing in due course of time. However, it is quite difficult to understand biological mechanisms and keep a track of these events in some storage mediums. DNA (deoxyribonucleic acid) is the best candidate for the storage of cellular events in the biological system. It is energy efficient as well as stable at the same time. DNA-based writers and memory devices are continually evolving and finding new avenues in terms of their wide range of applications. Among all the DNA-based storage devices that employ enzymes like recombinases, nucleases, integrases, and polymerases, one of the most popular tools used for these devices is the emerging and versatile CRISPR Cas technology. CRISPR Cas is a prokaryotic immune system that keeps a memory of viral attacks and protects prokaryotes from potential future infections. The main aim of this short review is to study such molecular recorders and writers that employ CRISPR Cas technologies and obtain an in-depth overview of the mechanisms involved and the applications of these molecular devices.