Breast cancer (BC) has become the most common malignant tumor in women worldwide. This study was carried out to find and validate a novel molecular therapeutic target for BC.

Long non-coding RNA (lncRNA) AK023507 was selected as the study objects through microarray analysis. The function of lncRNA AK023507 was verified by various cell function experiments in vitro, subcutaneous tumorigenesis experiments, and lung metastasis model experiments in vivo. The RNA pull-down experiment and Western blot experiment were used to confirm the mechanism regulation pathway and the recovery experiment was used to verify it. TCGA datasets were used for clinical and immune function prediction analysis.

In vitro cell function tests and in vivo experiments suggested that overexpression of lncRNA AK023507 inhibited the proliferation and metastasis of BC cells. The RNA pull-down experiment and Western blot analysis validated that lncRNA AK023507 interacted with the dedicator of cytokinesis 4 (DOCK4) protein. Analysis of public databases predicted that DOCK4 is a potential prognostic risk factor associated with epithelial-mesenchymal transition (EMT) and central memory T cell (TCM) cellular immune infiltration.

LncRNA AK023507 inhibits the proliferation and metastasis of BC by regulating the DOCK4/β-catenin axis. This discovery will provide new potential therapeutic targets for BC.

Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear.

This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024.

The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.

Genotoxic stress-induced stem cell maldifferentiation (GSMD) integrates DNA damage responses with loss of stemness and lineage-specific differentiation to prevent damaged stem cell propagation. However, molecular mechanisms governing GSMD remain unclear. Here, we identify the p53-induced long non-coding RNA LOC644656 as a key regulator of GSMD in human embryonic stem cells. LOC644656 accumulates in the nucleus upon DNA damage, disrupting pluripotency by interacting directly with POU5F1 and KDM1A/LSD1-NuRD complexes, repressing stemness genes, and activating TGF-β signaling. Additionally, LOC644656 mitigates DNA damage by binding DNA-PKcs and modulating the DNA damage response. In cancer, elevated LOC644656 correlates with poor patient survival and enhanced chemoresistance. Our findings demonstrate that LOC644656 mediates stemness suppression and resistance to genotoxic stress by coordinating DNA damage signaling and differentiation pathways. Thus, LOC644656 represents a potential therapeutic target for overcoming chemoresistance and advancing stem cell biology.

Pre-pregnancy obesity (ppOB) is linked to pregnancy complications and abnormal fetal growth through placental mechanisms, and long non-coding RNAs (lncRNAs) may play an epigenetic role in these processes. We investigated overall and sex-specific associations of pre-pregnancy body mass index (ppBMI), ppOB, and birthweight with placental lncRNA transcripts in two birth cohorts. Study participants were mother-child dyads recruited to the CANDLE (Memphis, TN)(n = 725) and GAPPS (Seattle and Yakima, WA)(n = 159) cohorts. Maternal ppBMI was assessed at enrollment using interviewer-administered questionnaires. LncRNAs (1,077 and 1,033 for CANDLE and GAPPS, respectively) were sequenced from placental samples collected at birth. Placental lncRNA was regressed on ppBMI, ppOB (ppBMI ≥30kg/m2), or continuous birthweight in cohort-specific weighted linear models controlling for a priori-specified confounders and experimental variables. Potential effect modification by infant-sex was examined in sex-stratified analyses and models including BMI-infant-sex interaction terms. No lncRNA transcripts were significantly associated with ppBMI, ppOB, or birthweight in primary models. Among male infants in CANDLE, expression of three lncRNA transcripts (ERVH48-1, AC139099.1, CEBPA-DT) was associated with ppBMI and one transcript (AC104083.1) with birthweight. In GAPPS, ppBMI was associated with two lncRNA transcripts (AP000879.1 and AL365203.2) among males, and birthweight was associated with 17 lncRNA transcripts (including LINC02709, KANSL1-AS1, DANCR, EPB41L4A-AS1, and GABPB1-AS1) among females. No BMI-infant-sex interactions were observed. Though many of these potential associations are for uncharacterized transcripts, several identified lncRNAs (e.g., ERVH48-1 and CEBPA-DT) have been linked to pathways controlling cancer or placental growth, trophoblast differentiation, and gene expression. These associations warrant validation in future studies.

Cotton plants undergo a drastic transcriptional reprogramming after cotton boll weevil infestation, modulating several defense pathways to cope with the damage. The global demand for cotton fiber continues to rise, but pests and pathogens significantly hinder cotton production, causing substantial losses. Among these, the cotton boll weevil (Anthonomus grandis) is one of the most destructive pests. To investigate the molecular responses of cotton (Gossypium hirsutum) to boll weevil infestation, we evaluated the global gene expression of floral buds using mRNA-seq. Additionally, we analyzed the expression of non-coding RNAs, including microRNAs (miRNAs) and long intergenic non-coding RNAs (lincRNAs). Infestation by cotton boll weevil larvae triggered a rapid and drastic transcriptional reprogramming, with 1,656 and 1.698 genes modulated after two and twelve hours, respectively. Gene ontology enrichment analysis revealed significant regulation of defense-related and developmental processes, including photosynthesis, primary metabolism, and cell organization. Transcription factor families such as ERF, WRKY, GRAS, and NAC were strongly affected, highlighting their roles in coordinating defense responses. The jasmonate pathway showed intensive modulation, alongside secondary metabolite pathways like terpenoids and phenylpropanoids, which contribute to plant defense mechanisms. Non-coding RNAs also played a critical role in the response. We identified 921 unique known and novel miRNAs, with 36 modulated by the infestation, and predicted 98,850 putative lincRNAs, several of which were differentially expressed. Understanding the genetic and molecular mechanisms underlying cotton's defense against boll weevil, particularly during early infestation stages, is vital for developing biotechnological strategies to reduce pest damage. Our findings provide critical insights to enhance cotton resilience against herbivores.

Noncoding RNAs (ncRNAs) are a class of RNA molecules with little or no protein-coding potential. Emerging evidence indicates that ncRNAs are frequently dysregulated and play pivotal roles in the pathogenesis of pancreatic cancer. Their aberrant expression can arise from chromosomal abnormalities, dysregulated transcriptional control, and epigenetic modifications. ncRNAs function as protein scaffolds or molecular decoys to modulate interactions between proteins and other biomolecules, thereby regulating gene expression and contributing to pancreatic cancer progression. In this review, we summarize the mechanisms underlying ncRNA dysregulation in pancreatic cancer, emphasize the biological significance of ncRNA-protein interactions, and highlight their clinical relevance. A deeper understanding of ncRNA-protein interactions is essential to elucidate molecular mechanisms and advance translational research in pancreatic cancer.

As the primary site of lipogenesis in birds, the liver orchestrates avian lipid metabolism and is pivotal for fat accumulation in chickens. Lipid metabolism during the broiler embryo stage may significantly affect post-hatch growth performance, yet research on this subject remains limited. While long non-coding RNAs (lncRNAs) have been found to regulate liver lipid metabolism in post-hatch chickens, their functions during the embryonic stage remains unclear. This study revealed that, compared to lean line broiler embryos, fat line broiler embryos showed upregulated gene expression related to de novo fatty acid synthesis, glycerol-3-phosphate synthesis, triglyceride synthesis, and the degradation of both fatty acids and cholesterol. Through transcriptome analysis and functional validation, lncRNA1926 and lncRNA3223 were identified as key regulators of lipid metabolism in broiler embryo livers. Knocking down either of lncRNA1926 or lncRNA3223 significantly reduced lipid droplet accumulation, triglyceride levels, and total cholesterol levels in primary hepatocytes of broiler embryos. Our findings demonstrate distinct lipid metabolic gene expression profiles between fat and lean line broiler embryo livers, and highlight lncRNA1926 and lncRNA3223 are key regulators of lipid metabolism during the embryonic stage. This study enhances the scientific understanding of lipid metabolism regulation in chicken livers and provides a theoretical foundation for genetically improving abdominal fat traits in broilers.

The gut microbiota features an abundance of diverse microorganisms and represents an important component of human physiology and metabolic homeostasis, indicating their roles in a wide array of physiological and pathological processes in the host. Maintaining balance in the gut microbiota is critical for normal functionality as microbial dysbiosis can lead to the occurrence and development of diseases through various mechanisms. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are non-coding RNAs that perform important regulatory functions for many processes. Furthermore, the gut microbiota and lncRNAs/circRNAs are known to interact in a range of both physiological and pathological activities. In this article, we review existing research relevant to the interaction between the gut microbiota and lncRNAs/circRNAs and investigate the role of their crosstalk in the pathogenesis of different diseases. Studies have shown that, the gut microbiota can target lncRNAs ENO1-IT1, BFAL1, and LINC00152 to regulate colorectal cancer development via various signaling pathways. In addition, the gut microbiota can influence mental diseases and lung tumor metastasis by modulating circRNAs such as circNF1-419, circ_0001239, circHIPK2 and mmu_circ_0000730. These findings provide a theoretical basis for disease prevention and treatment and suggest that gut microbiota-lncRNA/circRNA crosstalk has high clinical value.

Despite significant advances in cardiology over the past few decades, cardiovascular diseases (CVDs) remain the leading cause of global mortality and morbidity. This underscores the need for novel therapeutic interventions that go beyond symptom management to address the underlying causal mechanisms of CVDs. RNA-based therapeutics represent a new class of drugs capable of regulating specific genetic and molecular pathways, positioning them as strong candidates for targeting the root causes of a wide range of diseases. Moreover, owing to the vast diversity in RNA form and function, these molecules can be utilized to induce changes at different levels of gene expression regulation, making them suitable for a broad array of medical applications, even within a single disease context. Several RNA-based therapies are currently being investigated for their potential to address various CVD pathologies. These include treatments aimed at promoting cardiac revascularization and regeneration, preventing cardiomyocyte apoptosis, reducing harmful circulating cholesterols and fats, lowering blood pressure, reversing cardiac fibrosis and remodeling, and correcting the genetic basis of inherited CVDs. In this review, we discuss the current landscape of RNA therapeutics for CVDs, with an emphasis on their classifications, modes of action, advancements in delivery strategies and considerations for their implementation, as well as CVD targets with proven therapeutic potential.

Gene transcription is controlled and modulated by regulatory regions, including enhancers and promoters. These regions are abundant in non-coding bidirectional transcription that results in generally unstable RNA. Using nascent RNA transcription data across hundreds of human samples, we identified over 800,000 regions containing bidirectional transcription. We then identify tissue specific, highly correlated transcription between bidirectional and gene regions. The identified correlated pairs, a bidirectional region and a gene, are enriched for disease associated SNPs and often supported by independent 3D data. We present these resources as a database called DBNascent ( https://nascent.colorado.edu/ ) which serves as a resource for future studies into gene regulation, enhancer associated RNAs, and transcription factors.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, accounting for 90% of all cases. Currently, early diagnosis of HCC can be achieved through serum alpha-fetoprotein detection, B-ultrasound, and computed tomography scanning; however, their specificity and sensitivity are suboptimal. Despite significant advancements in HCC biomarker detection, the prognosis for patients with HCC remains unfavorable due to tumor heterogeneity and limited understanding of its pathogenesis. Therefore, it is crucial to explore more sensitive HCC biomarkers for improved diagnosis, monitoring, and management of the disease. Long non-coding RNA (lncRNA) serves as an auxiliary carrier of genetic information and also plays diverse intricate regulatory roles that greatly contribute to genome complexity. Moreover, investigating gene expression regulation networks from the perspective of lncRNA may provide insights into the diagnosis and prognosis of HCC. We searched the PubMed database for literature, comprehensively classified regulated cell death mechanisms and systematically reviewed research progress on lncRNA-mediated cell death pathways in HCC cells. Furthermore, we prospectively summarize its potential implications in diagnosing and treating HCC.

This retrospective study measured global gene abundance using RNASeq of blastocoel fluid-conditioned media from euploid ICSI-generated embryos to identify genes and signaling pathways associated with maternal age.

Blastocoel fluid-conditioned media was obtained following trophectoderm biopsy of ICSI-generated day-5 blastocysts. Media for RNASeq were from 24 euploid blastocysts (9 from patients aged 35 or older). Transcriptome analysis identified differentially expressed genes when comparing media from patients of advanced maternal age to those younger than 35. Further gene abundance analysis on genes and pathways identified from the RNASeq analysis was conducted with another group of media samples using RT-qPCR.

Twenty-five protein encoding genes identified in the RNASeq study were differentially expressed when comparing blastocoel fluid-conditioned media associated with patients of advanced maternal age to media associated with patients under the age of 35. Genes encoding the proteins SHARPIN and BCL2L12 showed a statistically significant increase (p < 0.05) in abundance in patients of advanced maternal age. Abundance analysis using RT-qPCR in additional media samples revealed elevated SHARPIN abundance in media associated with successful implantation in patients under 35 alongside a decrease in CASP8 abundance. This abundance pattern was the opposite in media associated with successful implantation in patients of advanced maternal age.

This study uncovered differential apoptotic gene abundance associated with maternal age by assessing blastocoel fluid-conditioned media from euploid blastocysts. These unique abundance patterns may provide insight into the regulation of apoptosis in embryos from women of advanced maternal age, and how this signaling pathway may impact implantation outcomes.

Understanding the core principles of ovarian cancer has been significantly improved through the exploration of Ferroptosis, a type of cell death triggered by iron that leads to an increase in lipid peroxides. Current research has shed light on the critical functions of non-coding RNAs, such as circRNAs, lncRNAs, and miRNAs, in regulating ferroptosis in ovarian cancer. The aim of this paper is to comprehensively analyze how ncRNAs influence the development of ferroptosis in ovarian cancer cells. In-depth exploration is undertaken to understand the intricate ways in which ncRNAs regulate essential elements of ferroptosis, including iron management and lipid peroxidation levels. We also investigate their significant involvement in the progression of this type of cellular demise. It should be emphasized that ncRNAs can impact the synthesis of crucial proteins, such as GPX4, a key contributor to the cellular defense against oxidation, and ACSL4, involved in lipid formation. In addition, we examine the correlation between ncRNAs and well-known pathways associated with oxidative stress and cell death. The consequences of these discoveries are noteworthy, since focusing on particular ncRNAs could potentially render ovarian cancer cells more vulnerable to ferroptosis, effectively combating drug resistance problems. This discussion highlights the growing significance of ncRNAs in governing ferroptosis and their potential as useful biomarkers and treatment targets for ovarian cancer. We intend to promote additional research into the involvement of ncRNAs in controlling ferroptosis, based on current findings, with the ultimate goal of informing targeted therapeutic strategies and improving long-term treatment outcomes for individuals suffering from OC.

Head and neck squamous cell carcinoma (HNSCC) is a major global health burden, often associated with poor prognosis and limited therapeutic options. Long non-coding RNAs (lncRNAs), a diverse group of non-coding RNA molecules > 200 nucleotides in length, have emerged as critical regulators in the pathogenesis of HNSCC. This review summarizes the mechanisms through which certain lncRNAs regulate chromatin modification, mRNA splicing, and interactions with RNA-binding proteins and contribute to the development and progression of HNSCC. Interaction of lncRNAs with key oncogenic pathways, such as PI3K/AKT and Wnt/β-catenin, highlights their importance in tumor progression. The role of lncRNAs, such as ELDR, MALAT1, NEAT1, HOTAIR, and UCA1, which promote cell proliferation, metastasis, immune evasion, and therapy resistance is discussed. Moreover, several lncRNAs are being evaluated in clinical trials for their potential as biomarkers, reflecting their clinical significance. We further address the challenges and opportunities for targeting lncRNA therapeutically, highlighting the promise of lncRNA-based interventions for personalized cancer treatment. Gaining insight into the function of lncRNAs in HNSCC could pave the way for novel therapeutic strategies to potentially improve patient outcomes.

Several studies have made it possible to envision a translational application of plasma DNA sequencing in cancer diagnosis and monitoring. However, the extremely low concentration of circulating tumour DNA (ctDNA) fragments among the total cell-free DNA (cfDNA) remains a formidable challenge to overcome and statistical models have yet to be improved enough to become of practical use. In this study, we set about appraising the predictive value of a variety of binary classification models based on cfDNA sequencing using fragmentation features extracted around transcription start sites (TSSs). We investigated (1) features summarising mapped fragment density around each TSS, (2) long non-coding RNA (lncRNA) genes versus coding genes and (3) selection criteria to generate gene classes to be assigned by the model. Given that, in healthy samples, most of the cfDNA comes from lymphomyeloid lineages, we could identify the model parametrisation with the best accuracy in those lineages using publicly available datasets of healthy patients' cfDNA. Our results show that (1) the way tissue-specific gene classes are defined matters more than what fragmentation features are included, and (2) in particular, lncRNAs are more tissue specific than coding genes and stand out in terms of both sensitivity and specificity in our results.

Vitiligo is an autoimmune depigmenting skin disorder and can affect the mental health of the patients. Current research suggests that the development of vitiligo involves a combination of genetic susceptibility, immune imbalance, and oxidative stress. However, its pathogenesis has not been fully elucidated. Epigenetic modification has gained increasing attention as an emerging way to regulate gene expression at the transcriptional or post-transcriptional level. Currently known modes of epigenetic modification include the regulation of non-coding RNAs, DNA methylation, and histone modification. Studies suggest they play important roles in tumors, immune disorders, and inflammatory diseases. In recent years, the value of epigenetics in the diagnosis, treatment, and prognosis of vitiligo has been explored. They showed the potential to serve as biomarkers and play a therapeutic role. In this review, we summarize the epigenetic modification mechanisms involved in the pathogenesis of vitiligo, including physiological processes such as immune homeostasis, melanocyte survival, cell adhesion and migration, and metabolism. This will help us fully understand the progress of epigenetic research in vitiligo and lay the foundation for targeted therapeutic-related research.

Nucleic acids have the potential to form not only duplexes, but also various non-canonical secondary structures in living cells. Non-canonical structures play regulatory functions mainly in the central dogma. Therefore, nucleic acid targeting molecules are potential novel therapeutic drugs that can target 'undruggable' proteins in various diseases. One of the concerns of small molecules targeting nucleic acids is selectivity, because nucleic acids have only four different building blocks. Three- and four-stranded non-canonical structures, triplexes and quadruplexes, respectively, are promising targets of small molecules because their three-dimensional structures are significantly different from the canonical duplexes, which are the most abundant in cells. Here, we describe some basic properties of the triplexes and quadruplexes and small molecules targeting the triplexes and tetraplexes.

Tuberculosis (TB) persists as a significant health threat, affecting millions of people all over the world. Despite years of control measures, the elimination of TB has become a difficult task as morbidity and mortality rates remain unaffected for several years. Developing new diagnostics and therapeutics is paramount to keeping TB under control. However, it largely depends upon understanding the pathogenic mechanisms of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Mtb is an intracellular pathogen capable of subverting the defensive functions of the immune cells, and it can survive and multiply within humans' mononuclear phagocytes. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of RNA molecules with limited coding potential, are critical players in this intricate game as they regulate gene expression at transcriptional and post-transcriptional levels and also by chromatin modification. Moreover, they have been shown to regulate cellular processes by controlling the function of other molecules, such as DNA, RNA, and protein, through binding with them. Recent studies have shown that lncRNAs are differentially regulated in the tissues of TB patients and cells infected in vitro with Mtb. Some dysregulated lncRNAs are associated with essential roles in modulating immune response, apoptosis, and autophagy in the host cells, adding a new dimension to TB pathogenesis. In this article, we provide a comprehensive review of the recent literature in this field and the impact of lncRNAs in unraveling pathogenic mechanisms in TB. We also discuss how the studies involving lncRNAs provide insight into TB pathogenesis, especially Mtb-host interactions.

Small open-reading frame-encoded micropeptides within long noncoding RNAs (lncRNAs) are often overlooked due to their small size and low abundance. However, emerging evidence links these micropeptides to various biological pathways, though their roles in neural development and neurodegeneration remain unclear. Here, we investigate the function of murine micropeptide Sertm2, encoded by the lncRNA A730046J19Rik, during spinal motor neuron (MN) development. Sertm2 is predicted to be a conserved transmembrane protein found in both mouse and human, with subcellular analysis revealing that it is enriched in the cytoplasm and neurites. By generating C terminally Flag-tagged Sertm2 and expressing it from the A730046J19Rik locus, we demonstrate that the Sertm2 micropeptide localizes in spinal MNs in mice. The GDNF signaling-induced Etv4+ motor pool is impaired in Sertm2 knockout mice, which display motor nerve arborization defects that culminate in impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also display reduced ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily conserved micropeptide essential for maintaining GDNF-induced MN subtype identity.

Breast cancer (BC) is a malignant tumor that has the highest morbidity and mortality rates in the female population, and its high tendency to metastasize is the main cause of poor clinical prognosis. Long non-coding RNAs (lncRNAs) have been extensively documented to exhibit aberrant expression in various cancers and influence tumor progression via multiple molecular pathways. These lncRNAs not only modulate numerous aspects of gene expression in cancer cells, such as transcription, translation, and post-translational modifications, but also play a crucial role in the reprogramming of energy metabolism by regulating metabolic regulators, which is particularly significant in advanced BC. This review examines the characteristics and mechanisms of lncRNAs in regulating BC cells, both intracellularly (e.g., cell cycle, autophagy) and extracellularly (e.g., tumor microenvironment). Furthermore, we explore the potential of specific lncRNAs and their regulatory factors as molecular markers and therapeutic targets. Lastly, we summarize the application of lncRNAs in the treatment of advanced BC, aiming to offer novel personalized therapeutic options for patients.

Long non-coding RNA (lncRNA) participates in various biological processes, however, neither the expression profile nor the biological role of lncRNAs in mammalian ovaries has been fully studied. In this work, the lncRNA transcriptomic analysis of postnatal mice ovaries was performed by using bulk RNA sequencing in C57BL/6 mice. A total of 5302 lncRNAs were found in mouse ovaries, and 1836 lncRNAs were differentially expressed during the development and ageing process, of which targets were enriched in the developmental process, reproduction, etc. Developmental stage specific lncRNAs showed functions in system development, inflammatory response, myeloid leukocyte activation, etc. Moreover, a co-expression network analysis based on reproduction-related genes reveals lncRNAs that may regulate multiple mRNA targets in ovaries, including Neat1, Gm11613 and Gm43915. Two cis-acting lncRNAs, Ptgs2os and Gm14705, showed correlated expression pattern with their potential targets Ptgs2 and Aff2 respectively, and these lncRNA-mRNA pairs were conserved in mice and humans. WGCNA further identified 10 co-expressed modules with distinct expression patterns associated with ovarian development and ageing. Taken together, our results reveal a transcriptomic profile of mouse ovaries over the reproductive lifespan, providing insights into the molecular mechanisms of ovarian development and ageing.

Accumulated studies have demonstrated that long noncoding RNAs (lncRNAs) play crucial regulatory roles in diverse biological processes, such as embryonic development and cell differentiation. Comprehensive transcriptome analysis identifies extensive lncRNAs, gradually elucidating their functions across various contexts. Recent studies have highlighted the essential role of lncRNAs in definitive endoderm differentiation, underscoring their importance in early development. In this review, we have analyzed the features of overlapping, proximal, and desert lncRNAs, classified by genomic location, in pluripotent stem cells (PSCs) and the differentiation derivatives. Furthermore, we focus on the endoderm lineage and review the latest advancements in lncRNA identification and their distinct regulatory mechanisms. By consolidating current knowledge, we aim to provide a clearer perspective on how lncRNAs contribute to endoderm differentiation in different manners.

Autoimmune diseases (ADs) are a group of complex, chronic conditions characterized by disturbance of immune tolerance, with examples including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. These diseases have unclear pathogenesis, and traditional therapeutic approaches remain limited. However, advances in high-throughput histology technology and scientific discoveries have led to the identification of various pathogenic factors contributing to ADs. Coupled with improvements in RNA nucleic acid-based drug synthesis, design, and delivery, RNA-based therapies have been extensively investigated for their potential in treating ADs. This paper reviews the progress in the use of miRNAs, lncRNAs, circRNAs, siRNAs, antisense oligonucleotides (ASOs), aptamers, mRNAs, and other RNA-based therapies in ADs, focusing on their therapeutic potential and application prospects, providing insights for future research and clinical treatment of autoimmune diseases.

The kidney is essential for maintaining fluid, electrolyte, and metabolite homeostasis, and for regulating blood pressure. The pig serves as a valuable biomedical model for human renal physiology, offering insights across different physiological states. In this study, single-cell RNA sequencing was used to profile 138 469 cells from 12 pig kidney samples collected during the embryonic (E), fattening (F), and pregnancy (P) periods, identifying 29 cell types. Proximal tubule (PT) cells exhibited elevated expression of metabolism-related transcription factors (TFs), including GPD1, ACAA1, and AGMAT, with validation across multiple individuals, periods, and species. Fluorescence homologous double-labeling of paraffin sections further confirmed the expression of ACAA1 and AGMAT in PT cells. Comparative analysis of pig and human kidneys revealed a high degree of similarity among corresponding cell types. Analysis of cell-type heterogeneity highlighted the diversity of thick ascending limb (TAL) cells, identifying a TAL subpopulation related to immune function. Additionally, the functional heterogeneity of kidney-resident macrophages (KRM) was explored across different anatomical sites. In the renal medulla, KRM were implicated in phagocytosis and leukocyte activation, whereas in the renal pelvis, they functioned as ligands, recruiting neutrophils with bactericidal activity to the renal pelvis to combat urinary tract infections.

Accurate gene annotations are fundamental for interpreting genetic variation, cellular function, and disease mechanisms. However, current human gene annotations are largely derived from transcriptomic data of individuals with European ancestry, introducing potential biases that remain uncharacterized. Here, we generate over 800 million full-length reads with long-read RNA-seq in 43 lymphoblastoid cell line samples from eight genetically-diverse human populations and build a cross-ancestry gene annotation. We show that transcripts from non-European samples are underrepresented in reference gene annotations, leading to systematic biases in allele-specific transcript usage analyses. Furthermore, we show that personal genome assemblies enhance transcript discovery compared to the generic GRCh38 reference assembly, even though genomic regions unique to each individual are heavily depleted of genes. These findings underscore the urgent need for a more inclusive gene annotation framework that accurately represents global transcriptome diversity.

More research has been done on the correlation between exercise and cancer, which has revealed several ways that physical activity decreases the risk of developing the disease. The developing function of lncRNAs as an important molecular link between exercise and cancer suppression is the main topic of this review. According to recent research, regular physical exercise also alters the expression levels of several lncRNAs, which are generally elevated in cancer. A complex network of interactions that may provide protective effects against carcinogenesis is suggested by the contribution of these lncRNAs in various cellular processes, such as epigenetic alterations, proliferation, and apoptosis regulation. We offer a comprehensive summary of the existing information regarding specific lncRNAs that are influenced by physical activity and could potentially impact cancer-related processes. We also go over the difficulties in interpreting these alterations, taking into account the fact that several lncRNAs have a dual function in promoting and preventing cancer in various physiological settings. To understand the complex impacts of exercise-induced lncRNA regulation in cancer biology, more study is required. The critique strongly highlights the possibility of lncRNAs serving as both indicators and treatment prospects for cancer-preventive strategies.

Long non-coding RNAs (lncRNAs), a type of non-coding RNA molecules, are known to play critical regulatory roles in various biological processes. However, the functions of the majority of lncRNAs remain largely unknown, and little is understood about the regulation of lncRNA expression. In this study, high-throughput DNA genotyping and RNA sequencing were applied to investigate genomic regions associated with lncRNA expression, commonly referred to as lncRNA expression quantitative trait loci (eQTLs). We analyzed the liver, lung, spleen, and muscle transcriptomes of 100 three-way crossbred sows to identify lncRNA transcripts, explore genomic regions that might influence lncRNA expression, and identify potential regulators interacting with these regions.

We identified 6380 lncRNA transcripts and 3733 lncRNA genes. Correlation tests between the expression of lncRNAs and protein-coding genes were performed. Subsequently, functional enrichment analyses were carried out on protein-coding genes highly correlated with lncRNAs. Our correlation results of these protein-coding genes uncovered terms that are related to tissue specific functions. Additionally, heatmaps of lncRNAs and protein-coding genes at different correlation levels revealed several distinct clusters. An expression genome-wide association study (eGWAS) was conducted using 535,896 genotypes and 1829, 1944, 2089, and 2074 expressed lncRNA genes for liver, spleen, lung, and muscle, respectively. This analysis identified 520,562 significant associations and 6654, 4525, 4842, and 7125 eQTLs for the respective tissues. Only a small portion of these eQTLs were classified as cis-eQTLs. Fifteen regions with the highest eQTL density were selected as eGWAS hotspots and potential mechanisms of lncRNA regulation in these hotspots were explored. However, we did not identify any interactions between the transcription factors or miRNAs in the hotspots and the lncRNAs, nor did we observe a significant enrichment of regulatory elements in these hotspots. While we could not pinpoint the key factors regulating lncRNA expression, our results suggest that the regulation of lncRNAs involves more complex mechanisms.

Our findings provide insights into several features and potential functions of lncRNAs in various tissues. However, the mechanisms by which lncRNA eQTLs regulate lncRNA expression remain unclear. Further research is needed to explore the regulation of lncRNA expression and the mechanisms underlying lncRNA interactions with small molecules and regulatory proteins.

Eukaryotic cells are highly structured and composed of multiple membrane-bound and membraneless organelles. Subcellular RNA localization is a critical regulator of RNA function, influencing various biological processes. At any given moment, RNAs must accurately navigate the three-dimensional subcellular environment to ensure proper localization and function, governed by numerous factors, including splicing, RNA stability, modifications, and localizing sequences. Aberrant RNA localization can contribute to the development of numerous diseases. Here, we explore diverse RNA localization mechanisms and summarize advancements in methods for determining subcellular RNA localization, highlighting imaging techniques transforming our ability to study RNA dynamics at the single-molecule level.

The systematic identification and functional characterization of noncanonical translation products, such as novel peptides, will facilitate the understanding of the human genome and provide new insights into cell biology. Here, we constructed a high-coverage peptide sequencing reference library with 11,668,944 open reading frames and employed an ultrafiltration tandem mass spectrometry assay to identify novel peptides. Through these methods, we discovered 8945 previously unannotated peptides from normal gastric tissues, gastric cancer tissues and cell lines, nearly half of which were derived from noncoding RNAs. Moreover, our CRISPR screening revealed that 1161 peptides are involved in tumor cell proliferation. The presence and physiological function of a subset of these peptides, selected based on screening scores, amino acid length, and various indicators, were verified through Flag-knockin and multiple other methods. To further characterize the potential regulatory mechanisms involved, we constructed a framework based on artificial intelligence structure prediction and peptide‒protein interaction network analysis for the top 100 candidates and revealed that these cancer-related peptides have diverse subcellular locations and participate in organelle-specific processes. Further investigation verified the interacting partners of pep1-nc-OLMALINC, pep5-nc-TRHDE-AS1, pep-nc-ZNF436-AS1 and pep2-nc-AC027045.3, and the functions of these peptides in mitochondrial complex assembly, energy metabolism, and cholesterol metabolism, respectively. We showed that pep5-nc-TRHDE-AS1 and pep2-nc-AC027045.3 had substantial impacts on tumor growth in xenograft models. Furthermore, the dysregulation of these four peptides is closely correlated with clinical prognosis. Taken together, our study provides a comprehensive characterization of the noncanonical proteome, and highlights critical roles of these previously unannotated peptides in cancer biology.

InfoScan is a novel bioinformatics tool designed for the comprehensive analysis of full-length single-cell RNA sequencing (scRNA-seq) data. It enables the identification of unannotated transcripts and rare cell populations, providing a powerful platform for transcriptome characterization. In this study, InfoScan was applied to glioblastoma multiforme (GBM), identifying a rare "neoplastic-stemness" subpopulation exhibiting cancer stem cell-like features. Functional analyses suggested that tumor-associated macrophages (TAMs) secrete SPP1, which binds to CD44 on neoplastic-stemness cells, activating the PI3K/AKT pathway and driving lncRNA transcription to promote metastasis. Integration of TCGA and CGGA datasets further supported these findings, highlighting key mutations associated with the neoplastic-stemness subpopulation. Drug sensitivity assays indicated that neoplastic-stemness cells might be sensitive to omipalisib, a PI3K inhibitor, pointing to a potential therapeutic target. InfoScan offers a robust framework for exploring complex transcriptomic landscapes and characterizing rare cell populations, providing valuable insights into GBM biology and advancing precision cancer therapy.

Polyamines play important roles in cell growth and proliferation. Polyamine metabolism genes are dysregulated in various tumors. Some polyamine metabolism genes are regulated by transcription factors. However, the transcription factors that regulate polyamine metabolism genes have not been completely identified. Additionally, whether any of the transcriptional regulations depend on tumor heterogeneity and the tumor microenvironment has not been investigated.

We used bulk RNA-seq data to identify dysregulated polyamine metabolism genes and their transcription factors across breast cancer subtypes. Genes highly correlated with polyamine changes were obtained, and their subtype-specific expressions were checked in tumor microenvironment cells using single-cell RNA (scRNA)-seq data. Gene Ontology enrichment analysis was used to explore their molecular functions and biological processes, and survival analysis was used to examine the impact of these genes on therapeutic outcome.

We first analyzed the dysregulation of polyamine synthesis, catabolism, and transport in four breast cancer subtypes. Genes such as AGMAT and CAV1 were dysregulated across all subtypes, while APRT, SAT1, and other genes were dysregulated in the more lethal subtypes. Among the dysregulated genes of polyamine metabolism, we focused on three genes (SRM, APRT, and SAT1) and identified their transcription factors (SPI1 and IRF1 correspond to SAT1, and IRF3 corresponds to SRM and APRT). With scRNA-seq data, we verified that these three transcription factors also regulated these three polyamine metabolism genes in the tumor microenvironment. Both bulk RNA-seq and scRNA-seq data indicated that these genes were specifically upregulated in high-risk breast cancer subtypes, such as the basal-like type. High expression of these genes corresponded to worse outcomes in the basal-like subtype under chemotherapy and radiation treatment.

Our work identified three subtype-specific transcription factors that regulate three polyamine metabolism genes in high-risk breast cancer subtypes and the tumor microenvironment. Our results deepen the understanding of the role of polyamine metabolism in breast cancer and may help the clinical therapy of advanced breast cancer subtypes.

Dysregulation of RNA processing has in recent years emerged as a significant contributor to neurodegeneration. The diverse mechanisms and molecular functions underlying RNA processing underscore the essential role of RNA regulation in maintaining neuronal health and function. RNA molecules are bound by RNA-binding proteins (RBPs), and interactions between RNAs and RBPs are commonly affected in neurodegeneration. In this review, we highlight recent progress in understanding dysregulated RNA-processing pathways and the causes of RBP dysfunction across various neurodegenerative diseases. We discuss both established and emerging mechanisms of RNA-mediated neuropathogenesis in this rapidly evolving field. Furthermore, we explore the development of potential RNA-targeting therapeutic approaches for the treatment of neurodegenerative diseases.

Brain cancer remains a formidable challenge with limited treatment options. Non-coding RNAs (ncRNAs) have emerged as promising biomarkers due to their dysregulation in tumorigenesis. This review explores the potential of biosensors for early detection of brain cancer by targeting ncRNAs. We discuss the classification and functions of ncRNAs, emphasizing their involvement in key cancer-related processes. Additionally, we delve into recent advancements in biosensor technology, focusing on their ability to accurately detect specific ncRNA biomarkers associated with brain cancer. Our findings underscore the potential of biosensors to revolutionize brain cancer diagnosis, enabling personalized medicine and improving patient outcomes. Future research should focus on refining biosensor technology and expanding their clinical application.

Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses, KLF16 emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression of Klf16 in vitro inhibited osteogenic differentiation and mineralization, while Klf16 +/- mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such as KLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.

Mitochondrial dysfunction is implicated in numerous disorders, including type 2 diabetes, Alzheimer's disease and cancer. Long non-coding RNAs (lncRNAs) are emerging as pivotal regulators of cellular energy metabolism, yet their roles remain largely unclear. In this study, we identify an lncRNA named linc-PMB, which is associated with mTOR and promotes mitochondrial biogenesis, through microarray analysis. We demonstrate that the knockdown of linc-PMB results in significantly impaired mitochondrial respiration and biogenesis, along with altered expressions of related genes. Conversely, overexpression of linc-PMB markedly increases mitochondrial function. We further reveal that linc-PMB interacts with the RNA-binding protein HuR, promoting the stabilization of SIRT1 mRNA and a substantial increase in SIRT1 expression, which in turn activates the PGC-1α/mtTFA pathway and mitochondrial biogenesis. Collectively, our findings reveal a novel regulatory pathway in which linc-PMB, through its interaction with HuR, modulates the SIRT1/PGC-1α/mtTFA axis to maintain mitochondrial biogenesis and function.

Despite growing interest in the onco-fusion proteins and long noncoding RNAs (lncRNAs) in cancers, lncRNA-derived fusion transcripts in pediatric cancers remain understudied. To address this gap, we first developed LncFusion , a novel computational pipeline that systematically detects lncRNA-derived fusion transcripts from RNA-seq data. Leveraging our previously published Flnc (for comprehensive lncRNA identification) as a foundation and applying LncFusion , we identified over 900 high-confidence lncRNA-derived fusions (lnc-fusions) in pediatric neuroblastoma by analyzing the transcriptomics datasets from three major pediatric cancer cohorts-TARGET, Gabriella Miller Kids First, and St. Jude Cloud. The number of lnc-fusions exceeds the number of mRNA-derived fusions (mRNA-fusions) in neuroblastoma. Whole genome sequencing analyses revealed that approximately 40% of these lnc-fusions result from chromosomal rearrangements, while over 60% may arise from aberrant splicing events. Among these high-confidence lnc-fusions, 61 are enriched in pediatric neuroblastoma compared to healthy controls; and 20s exhibit subtype-specific expressions in pediatric neuroblastoma patients, which would be categorized into three groups: MYCN-amplified patients, c-MYC-highly expressed patients and the remaining (MYCN-unamplified and c-MYC not high expression). Subtype-specific enrichment of certain lnc-fusions, particularly in MYCN-amplified and c-MYC-high subgroups, underscores distinct oncogenic roles. Further functional studies implicated lnc-fusions in key pathways related to neuron development, translation, and energy metabolism, suggesting potential contributions to neuroblastoma pathogenesis. Additionally, We found several novel fusions might serve as potential diagnostic or prognostic biomarkers in neuroblastoma. A few candidates correlate with either favorable histology and lower-risk patient subsets, or poorer survival outcomes, indicating strong prognostic biomarker potential. Experiments in cell line further confirmed the presence of a few key lnc-fusions discovered from patient samples. Our findings provide the first comprehensive insight into lncRNA-derived fusions in pediatric neuroblastoma, providing the promise of lnc-fusions as novel biomarkers and therapeutic targets. The LncFusion tool developed can also be applied to explore lnc-fusions in other pediatric and adult cancers.

Cancer-associated fibroblasts (CAFs) play important roles in the occurrence and development of hepatocellular carcinoma (HCC) and are a key component of the immunosuppressive microenvironment. However, the origin of CAFs has not been fully elucidated. We employed single-cell sequencing technology to identify the dynamic changes in different subsets of fibroblasts at different time points in rat primary HCC model. Inflammation-associated CAFs (Pdgfrα+ CAFs) were subsequently identified, which demonstrated a significant correlation with the survival duration of HCC patients and a dual role in the tumour microenvironment (TME). On the one hand, they secrete the chemokines CCL3 and CXCL12, which recruit macrophages to the tumour site. On the other hand, they produce TGFβ, inducing the polarization of these macrophages towards an immunosuppressive phenotype. According to the in vitro and in vivo results, hepatic progenitor cells (HPCs) can aberrantly differentiate into PDGFRα+ CAFs upon stimulation with inflammatory cytokine. This differentiation is mediated by the activation of the MAPK signaling pathway and the downstream transcription factor ERG via the TLR4 receptor. Downregulating the expression of ERG in HPCs significantly reduces the number of PDGFRα+ CAFs and the infiltration of tumour-associated macrophages in HCC, thereby suppressing hepatocarcinogenesis. Collectively, our findings elucidate the distinct biological functions of PDGFRα+ cancer-associated fibroblasts (PDGFRα+ CAFs) within the TME. These insights contribute to our understanding of the mechanisms underlying the establishment of an immunosuppressive microenvironment in HCC, paving the way for the exploration of novel immunotherapeutic strategies tailored for HCC treatment.

Hepatocellular carcinoma (HCC) remains a malignant and life-threatening tumor with an extremely poor prognosis, posing a significant global health challenge. Despite the continuous emergence of novel therapeutic agents, patients exhibit substantial heterogeneity in their responses to anti-tumor drugs and overall prognosis. The pentose phosphate pathway (PPP) is highly activated in various tumor cells and plays a pivotal role in tumor metabolic reprogramming. This study aimed to construct a model based on PPP-related Genes for risk assessment and prognosis prediction in HCC patients. We integrated RNA-seq and microarray data from TCGA, GEO, and ICGC databases, along with single-cell RNA sequencing (scRNA-seq) data obtained from HCC patients via GEO. Based on the "Seurat" R package, we identified distinct gene clusters related to the PPP within the scRNA-seq data. Using a penalized Cox regression model with least absolute shrinkage and selection operator (LASSO) penalties, we constructed a risk prognosis model. The validity of our risk prognosis model was further confirmed in external cohorts. Additionally, we developed a nomogram capable of accurately predicting overall survival in HCC patients. Furthermore, we explored the predictive potential of our risk model within the immune microenvironment and assessed its relevance to biological function, particularly in the context of immunotherapy. Subsequently, we performed in vitro functional validation of the key genes (ATAD2 and SPP1) in our model. A ten-gene signature associated with the PPP was formulated to enhance the prediction of HCC prognosis and anti-tumor treatment response. Following this, the ROC curve, nomogram, and calibration curve outcomes corroborated the model's robust clinical predictive capability. Functional enrichment analysis unveiled the engagement of the immune system and notable variances in the immune infiltration landscape across the high and low-risk groups. Additionally, tumor mutation frequencies were observed to be elevated in the high-risk group. Based on our analyses, the IC50 values of most identified anticancer agents demonstrated a correlation with the RiskScore. Additionally, the high-risk and low-risk groups exhibited differential sensitivity to various drugs. Cytological experiments revealed that silencing ATAD2 or SPP1 suppresses malignant phenotypes, including viability and migration, in liver cancer cells. In this study, a novel gene signature related to the PPP was developed, demonstrating favorable predictive performance. This signature holds significant guiding value for assessing the prognosis of HCC patients and directing individualized treatment strategies.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype. Recent advances in transcriptome sequencing have highlighted the critical role of long non-coding RNAs (lncRNAs) in NSCLC, with lncRNAs influencing gene expression through epigenetic, transcriptional, and post-transcriptional mechanisms. Despite the growing understanding of lncRNAs, challenges such as delayed diagnosis and drug resistance continue to complicate NSCLC management. This review explores novel findings in the role of lncRNAs (e.g., MALAT1, HOTAIR, and GAS5) in NSCLC, with a particular focus on their encoded small peptides and N6-methyladenosine (m6A) modifications. We further discuss how the interplay between lncRNAs, their encoded peptides, and m6A modifications can provide new strategies for improving NSCLC diagnosis, treatment, and overcoming drug resistance. This review also highlights emerging research avenues that could lead to innovative clinical interventions in NSCLC.