Context-dependent Functions Research Articles

PIWI proteins and piRNAs: key regulators of stem cell biology

In this mini review, we discussed the functional roles of PIWI proteins and their associated small RNAs, piRNAs, in regulating gene expression within stem cell biology. Guided by piRNAs, these proteins transcriptionally and post-transcriptionally repress transposons using mechanisms such as the ping-pong amplification cycle and phasing to protect germline genomes. Initially identified in Drosophila melanogaster, the piRNA pathway regulate germline stem cell self-renewal and differentiation via cell-autonomous and non-cell-autonomous mechanisms. Precisely, in GSCs, PIWI proteins and piRNAs regulate gene expression by modulating chromatin states and directly influencing mRNA translation. For instance, the PIWI protein Aubergine loaded with piRNAs promotes and represses translation of certain mRNAs to balance self-renewal and differentiation. Thus, the piRNA pathway exhibits dual regulatory roles in mRNA stability and translation, highlighting its context-dependent functions. Moreover, PIWI proteins are essential in somatic stem cells to support the regenerative capacity of highly regenerative species, such as planarians. Similarly, in Drosophila intestinal stem cells, the PIWI protein Piwi regulates metabolic pathways and genome integrity, impacting longevity and gut homeostasis. In this case, piRNAs appear absent in the gut, suggesting piRNA-independent regulatory mechanisms. Together, PIWI proteins and piRNAs demonstrate evolutionary conservation in stem cell regulation, integrating TE silencing and gene expression regulation at chromatin and mRNA levels in somatic and germline lineages. Beyond their canonical roles, emerging evidence reveal their broader significance in maintaining stem cell properties and organismal health under physiological and pathological conditions.

Loss of Sirtuin 7 impairs cell motility and proliferation and enhances S-phase cell arrest after 5-fluorouracil treatment in head and neck cancer

Sirtuin 7 (SIRT7), a member of the sirtuin family of NAD+-dependent deacetylases, plays a vital role in cancer, exhibiting context-dependent functions across various malignancies. Our study investigates the role of SIRT7 depletion in head and neck squamous cell carcinoma (HNSCC) progression. In vitro and 3D organotypic models demonstrated that SIRT7 knock-out attenuates cancer cell viability, proliferation, and motility as well as induces downregulation of migration- and epithelial-mesenchymal transition (EMT)-related gene expression. Moreover, the SIRT7 loss results in slower organoid formation and less invasive organoid morphology, validated by vimentin downregulation. The SIRT7 loss potentiates S-phase arrest in cell cycle progression after 5-FU treatment and elevates the ratio of dead cells. Additionally, SIRT7 deletion reduces the expression of G1 phase-associated proteins, Cyclin D and CDK4. Altogether, our study highlights SIRT7 as a promising therapeutic target in HNSCC, enhancing the effectiveness of treatment modalities such as combinational treatment.

DNA Methylation Analysis by Bisulfite Pyrosequencing of Mouse Embryonic Fibroblasts with Reprogramming Enhanced by Thyroid Hormones.

DNA methylation is a widely studied epigenetic mark which in mammals involves the incorporation of a methyl group to the fifth carbon of cytosines, mainly those belonging to CpG dinucleotides. It has been linked to context-dependent regulatory functions ranging from gene and repetitive DNA silencing to gene body transcriptional activity. Because of its important roles during embryonic development and cell differentiation, DNA methylation can be used to track cell reprogramming by measuring the methylation levels of pluripotency-associated factors. In this scenario, bisulfite pyrosequencing is a simple, robust, and widely used technique which allows for the quantification of DNA methylation levels at small, specific regions of the genome. It involves the amplification and biotin tagging of bisulfite-converted DNA. Single amplified strands are then purified using streptavidin and finally pyrosequenced using a sequencing primer. Thus, it is an ideal method for the quantitative profiling of specific genomic regions, with applications ranging from biomarker discovery and epigenetic clock tracking to omic validation studies.

Biological and clinical role of TREM2 in liver diseases.

Liver diseases constitute a major health burden worldwide, accounting for more than 4% of all disease-related mortalities. While the incidence of viral hepatitis is expected to decrease, metabolic liver disorders are increasingly diagnosed. Liver pathology is diverse, with functional and molecular alterations in both parenchymal and mesenchymal cells, including immune cells. Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and mainly expressed on myeloid cells. Several studies have demonstrated that TREM2 plays a critical role in tissue physiology and various pathological conditions. TREM2 is recognized as being associated with the development of liver diseases by regulating tissue homeostasis and the immune microenvironment. The biological and clinical impact of TREM2 is complex, given its diverse context-dependent functions. This review aims to summarize recent progress in understanding the association between TREM2 and different liver disorders and shed light on the clinical significance of targeting TREM2.

Dual Roles of microRNA-122 in Hepatocellular Carcinoma and Breast Cancer Progression and Metastasis: A Comprehensive Review.

microRNA-122 (miR-122) plays crucial yet contrasting roles in hepatocellular carcinoma (HCC) and breast cancer (BC), two prevalent and aggressive malignancies. This review synthesizes current research on miR-122's functions in these cancers, focusing on its potential as a diagnostic, prognostic, and therapeutic target. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus databases. In HCC, miR-122 is downregulated in most cases, suppressing oncogenic pathways and reducing tumor growth and metastasis. Restoring miR-122 levels has shown promising therapeutic potential, increasing sensitivity to treatments like sorafenib. In contrast, in BC, miR-122 plays a pro-metastatic role, especially in triple-negative breast cancer (TNBC) and metastatic lesions. miR-122's ability to influence key pathways, such as the Wnt/β-catenin and NF-κB pathways in HCC, and its role in enhancing the Warburg effect in BC underline its significance in cancer biology. miR-122, a key factor in breast cancer radioresistance, suppresses tumors in radiosensitive cells. Inhibiting miR-122 could reverse resistance and potentially overcome radiotherapy resistance. Given its context-dependent functions, miR-122 could serve as a potential therapeutic target, where restoring or inhibiting its expression may help in treating HCC and BC, respectively. The dual roles of miR-122 underscore its significance in cancer biology and its potential in precision medicine.

Literature review: nuclear factor kappa B (NF-κB) regulation in human cancers mediated by ubiquitin-specific proteases (USPs).

The nuclear factor kappa B (NF-κB) consists of a group of transcription factors of which its dysregulation is responsible for diseases such as inflammation and cancer. Ubiquitin-specific proteases (USPs) are the most prominent group among the deubiquitinases (DUBs). Their functions include control of protein stability and regulation of signaling transduction. The association between NF-κB activity and human cancer progression is evident. Still, the role of USPs in the NF-κB regulation in human cancers, especially prostate cancer, is not well understood. This review discusses on the role of USP-mediated regulation of the canonical NF-κB signaling pathway in human cancers and provides a prospect of future studies in prostate cancers. Within the biomedical literature database, PubMed, our review team searched for keywords including USP, NF-κB signaling pathway, cancer, prostate cancer, and specific USPs such as USP1, USP2, USP3, etc. These keywords were used individually or in combinations. After screening, only mechanistic studies and articles reporting the subsequent changes in cellular behaviors were included for full-text review. Most USPs function primarily as DUBs to regulate the canonical NF-κB signaling pathway. The typical K48- and K63-linked DUB activities of USPs are the best understood. These USPs are positive and negative regulators of the NF-κB activity. However, their DUB activities against polyubiquitin chains with atypical linkages have not yet been extensively studied. Furthermore, some USPs can regulate the canonical NF-κB signaling pathway via ubiquitin-independent mechanisms. In the regulation of the canonical NF-κB pathway, the USPs function primarily as DUBs, but they also regulate the p65/p50 by ubiquitin-independent mechanisms. Generally, in human cancer models, USP-mediated elevation and suppression of p65/p50 activity lead to more or less malignant cellular behaviors, respectively. Given the currently unbalanced focus on K48- and K63-linked DUB activities and the context-dependent function of USPs, future research of USP-mediated NF-κB regulation in human cancers should invest more in the DUB activities against the atypical polyubiquitin chains and test known mechanisms in different cancer models.

Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma.

Galectin-9 (Gal-9) is a tandem-repeat galectin with diverse roles in immune homeostasis, inflammation, malignancy, and autoimmune diseases. In cancer, Gal-9 displays variable expression patterns across different tumor types. Its interactions with multiple binding partners, both intracellularly and extracellularly, influence key cellular processes, including immune cell modulation and tumor microenvironment dynamics. Notably, Gal-9 binding to cell-specific glycoconjugate ligands has been implicated in both promoting and suppressing tumor progression. Here, we provide insights into Gal-9 and its involvement in immune homeostasis and cancer biology with an emphasis on multiple myeloma (MM) pathophysiology, highlighting its complex and context-dependent dual functions as a pro- and anti-tumorigenic molecule and its potential implications for therapy in MM patients.

Short-term plasticity and context-dependent circuit function: Insights from retinal circuitry.

Changes in synaptic strength across timescales are integral to algorithmic operations of neural circuits. However, pinpointing synaptic loci that undergo plasticity in intact brain circuits and delineating contributions of synaptic plasticity to circuit function remain challenging. The whole-mount retina preparation provides an accessible platform for measuring plasticity at specific synapses while monitoring circuit-level behaviors during visual processing ex vivo. In this review, we discuss insights gained from retina studies into the versatile roles of short-term synaptic plasticity in context-dependent circuit functions. Plasticity at single synapse level greatly expands the algorithms of common microcircuit motifs and contributes to diverse circuit-level behaviors such as gain modulation, selective gating, and stimulus-dependent excitatory/inhibitory balance. Examples in retinal circuitry offer unequivocal support that synaptic plasticity increases the computational capacity of hardwired neural circuitry.

Causal role of frontocentral beta oscillation in comprehending linguistic communicative functions

Linguistic communication is often considered as an action serving the function of conveying the speaker's goal to the addressee. Although neuroimaging studies have suggested a role of the motor system in comprehending communicative functions, the underlying mechanism is yet to be specified. Here, by two EEG experiments and a tACS experiment, we demonstrate that the frontocentral beta oscillation, which represents action states, plays a crucial part in linguistic communication understanding. Participants read scripts involving two interlocutors and rated the interlocutors’ attitudes. Each script included a critical sentence said by the speaker expressing a context-dependent function of either promise, request, or reply to the addressee's query. These functions were behaviorally discriminated, with higher addressee's will rating for the promise than for the reply and higher speaker's will rating for the request than for the reply. EEG multivariate analyses showed that different communicative functions were represented by different patterns of the frontocentral beta activity but not by patterns of alpha activity. Further tACS results showed that, relative to alpha tACS and sham stimulation, beta tACS improved the predictability of communicative functions of request or reply, as measured by the speaker's will rating. These results convergently suggest a causal role of the frontocentral beta activities in comprehending linguistic communications.

TIM-3 on myeloid cells promotes pulmonary inflammation through increased production of galectin-3

T cell immunoglobulin and mucin-containing molecule 3 (TIM-3) exhibits unique, cell type- and context-dependent characteristics and functions. Here, we report that TIM-3 on myeloid cells plays essential roles in modulating lung inflammation. We found that myeloid cell-specific TIM-3 knock-in (FSF-TIM3/LysM-Cre+) mice have lower body weight and shorter lifespan than WT mice. Intriguingly, the lungs of FSF-TIM3/LysM-Cre+ mice display excessive inflammation and features of disease-associated pathology. We further revealed that galectin-3 levels are notably elevated in TIM-3-overexpressing lung-derived myeloid cells. Furthermore, both TIM-3 blockade and GB1107, a galectin-3 inhibitor, ameliorated lung inflammation in FSF-TIM3/LysM-Cre+/− mice. Using an LPS-induced lung inflammation model with myeloid cell-specific TIM-3 knock-out mice, we demonstrated the association of TIM-3 with both lung inflammation and galectin-3. Collectively, our findings suggest that myeloid TIM-3 is an important regulator in the lungs and that modulation of TIM-3 and galectin-3 could offer therapeutic benefits for inflammation-associated lung diseases.

Beware! Different methods lead to divergent results on yawn contagion modulation in bonobos.

Contagious yawning (CY)-linked to physiological synchronization and possibly emotional contagion-occurs when one individual's yawn induces yawning in others. CY was investigated over different time windows (minutes from the triggering stimulus) via naturalistic or experimental studies (using real and video yawns, respectively) with contrasting results, especially in bonobos. We verified whether in bonobos result divergences may derive from different methods. We gathered yawning data on 13 bonobos at Twycross Zoo (UK) via a naturalistic (all-occurrences observations) and experimental approach (by showing yawn/control video stimuli). Based on literature, we used 1- and 3-min windows to detect CY. Due to fission-fusion management, individuals could form permanent or non-permanent associations (more/less familiar subjects under naturalistic setting). Video yawn stimuli may come from group mates/stranger models (more/less familiar subjects under the experimental setting). Stimulus type and time window affected CY modulating factors but not CY detection. Familiarity and age effect on CY showed opposite trends in 3-min trials and 1-min observations. CY was highest in oldest, non-permanently (rather than permanently) associated subjects in the naturalistic setting, but in the youngest subjects and with ingroup (rather than outgroup) models in trials. The age effect differences on CY might be due to decontextualized yawns and immature subject curiosity toward videos. The reversed familiarity effect suggests CY's context-dependent function in promoting social synchronization with socially distant group mates, as failing to coordinate as a group may lead to social disruption. Complementary methods are needed to fully understand motor replication phenomena.

Sequence reliance of the Drosophila context-dependent transcription factor CLAMP.

Despite binding similar cis elements in multiple locations, a single transcription factor (TF) often performs context-dependent functions at different loci. How factors integrate cis sequence and genomic context is still poorly understood and has implications for off-target effects in genetic engineering. The Drosophila context-dependent TF chromatin-linked adaptor for male-specific lethal proteins (CLAMP) targets similar GA-rich cis elements on the X-chromosome and at the histone gene locus but recruits very different, locus-specific factors. We discover that CLAMP leverages information from both cis element and local sequence to perform context-specific functions. Our observations imply the importance of other cues, including protein-protein interactions and the presence of additional cofactors.

Glyoxalase System in Breast and Ovarian Cancers: Role of MEK/ERK/SMAD1 Pathway.

The glyoxalase system, comprising GLO1 and GLO2 enzymes, is integral in detoxifying methylglyoxal (MGO) generated during glycolysis, with dysregulation implicated in various cancer types. The MEK/ERK/SMAD1 signaling pathway, crucial in cellular processes, influences tumorigenesis, metastasis, and angiogenesis. Altered GLO1 expression in cancer showcases its complex role in cellular adaptation and cancer aggressiveness. GLO2 exhibits context-dependent functions, contributing to both proapoptotic and antiapoptotic effects in different cancer scenarios. Research highlights the interconnected nature of these systems, particularly in ovarian cancer and breast cancer. The glyoxalase system's involvement in drug resistance and its impact on the MEK/ERK/SMAD1 signaling cascade underscore their clinical significance. Furthermore, this review delves into the urgent need for effective biomarkers, exemplified in ovarian cancer, where the RAGE-ligand pathway emerges as a potential diagnostic tool. While therapeutic strategies targeting these pathways hold promise, this review emphasizes the challenges posed by context-dependent effects and intricate crosstalk within the cellular milieu. Insights into the molecular intricacies of these pathways offer a foundation for developing innovative therapeutic approaches, providing hope for enhanced cancer diagnostics and tailored treatment strategies.

Nutrients: Signal 4 in T cell immunity.

T cells are integral in mediating adaptive immunity to infection, autoimmunity, and cancer. Upon immune challenge, T cells exit from a quiescent state, followed by clonal expansion and effector differentiation. These processes are shaped by three established immune signals, namely antigen stimulation (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Emerging findings reveal that nutrients, including glucose, amino acids, and lipids, are crucial regulators of T cell responses and interplay with Signals 1-3, highlighting nutrients as Signal 4 to license T cell immunity. Here, we first summarize the functional importance of Signal 4 and the underlying mechanisms of nutrient transport, sensing, and signaling in orchestrating T cell activation and quiescence exit. We also discuss the roles of nutrients in programming T cell differentiation and functional fitness and how nutrients can be targeted to improve disease therapy. Understanding how T cells respond to Signal 4 nutrients in microenvironments will provide insights into context-dependent functions of adaptive immunity and therapeutic interventions.

New Insights into the Role of KLF10 in Tissue Fibrosis.

Fibrosis, characterized by excessive extracellular matrix accumulation, disrupts normal tissue architecture, causes organ dysfunction, and contributes to numerous chronic diseases. This review focuses on Krüppel-like factor 10 (KLF10), a transcription factor significantly induced by transforming growth factor-β (TGF-β), and its role in fibrosis pathogenesis and progression across various tissues. KLF10, initially identified as TGF-β-inducible early gene-1 (TIEG1), is involved in key biological processes including cell proliferation, differentiation, apoptosis, and immune responses. Our analysis investigated KLF10 gene and protein structures, interaction partners, and context-dependent functions in fibrotic diseases. This review highlights recent findings that underscore KLF10 interaction with pivotal signaling pathways, such as TGF-β, and the modulation of gene expression in fibrotic tissues. We examined the dual role of KLF10 in promoting and inhibiting fibrosis depending on tissue type and fibrotic context. This review also discusses the therapeutic potential of targeting KLF10 in fibrotic diseases, based on its regulatory role in key pathogenic mechanisms. By consolidating current research, this review aims to enhance the understanding of the multifaceted role of KLF10 in fibrosis and stimulate further research into its potential as a therapeutic target in combating fibrotic diseases.

Multimodal profiling reveals site-specific adaptation and tissue residency hallmarks of γδ T cells across organs in mice

γδ T cells perform heterogeneous functions in homeostasis and disease across tissues. However, it is unclear whether these roles correspond to distinct γδ subsets or to a homogeneous population of cells exerting context-dependent functions. Here, by cross-organ multimodal single-cell profiling, we reveal that various mouse tissues harbor unique site-adapted γδ subsets. Epidermal and intestinal intraepithelial γδ T cells are transcriptionally homogeneous and exhibit epigenetic hallmarks of functional diversity. Through parabiosis experiments, we uncovered cellular states associated with cytotoxicity, innate-like rapid interferon-γ production and tissue repair functions displaying tissue residency hallmarks. Notably, our observations add nuance to the link between interleukin-17-producing γδ T cells and tissue residency. Moreover, transcriptional programs associated with tissue-resident γδ T cells are analogous to those of CD8+ tissue-resident memory T cells. Altogether, this study provides a multimodal landscape of tissue-adapted γδ T cells, revealing heterogeneity, lineage relationships and their tissue residency program.

Early growth response 1 transcription factor and its context-dependent functions in glioblastoma.

Glioblastoma is the most aggressive form of primary brain tumour in adults. This tumour employs numerous transcription factors to advance and sustain its progression. Current evidence suggest that early growth response 1 (EGR1) plays a dual role as both an oncogene and a tumour suppressor in glioblastoma. Early growth response 1 expression is prevalent in glioblastoma, affecting over 80% of cases. Early growth response 1 regulatory roles extend to angiogenesis, cell adhesion, and resistance to chemotherapy, notably influencing pathways like hypoxia-inducible factor 1α and vascular endothelial growth factor A. Early growth response 1 can also induce cell adhesion, migration, chemoresistance against temozolomide, stemness, and self-renewal in glioblastoma cells. Despite its oncogenic functions, EGR1 can also suppress tumours by upregulating non-steroidal anti-inflammatory drug-activated gene 1 and phosphatase and tensin homolog deleted on chromosome ten, and inhibiting invasion and metastasis. Additionally, EGR1 may have hypothetical implications in the viral hit-and-run theory, particularly regarding cytomegalovirus infection. The key findings of this review are the context- dependent nature of EGR1's actions and its potential as a prognostic marker in glioblastoma. Further research is needed to understand EGR1's role fully and exploit its potential in clinics.

Circular RNAs in Cervical Cancer: What are the Prospects?

C ervical cancer remains a pressing global health problem, creating a significant health burden for women worldwide. High incidence and mortality rates necessitate further research to unravel its underlying molecular mechanisms and identify new diagnostic and treatment strategies. Recent advances in non-coding RNAs have opened up new avenues for research, including circular RNAs (circRNAs) as molecules that play a multifaceted role in cellular processes. Research into circRNAs revealed their unique structure, characterized by the covalent formation of a closed loop, thereby distinguishing them from their linear counterparts. These circRNAs are involved in regulating various aspects of cell physiology with a particular focus on cell growth and development. Interestingly, circRNAs have context-dependent functions, acting both as promoters and inhibitors of oncogenic processes, depending on the complex cellular environment in which they operate. Recent studies have identified aberrant expression patterns of circRNAs in the context of cervical cancer, implying their key role in the disease development. The different expression profiles of circRNAs associated with cervical cancer offer promising opportunities for early detection, accurate prognosis assessment, and personalized treatment strategies. The presented comprehensive review offers an in-depth study of cervical cancer-associated circRNAs, their specific functions and complex molecular mechanisms driving the onset and progression of cervical cancer. Increasing evidence suggests that circRNAs can serve as invaluable biomarkers for early detection of cervical cancer and promising therapeutic targets for intervention. Delving into the complex interaction between circRNAs and cervical cancer paves the way for innovative and personalized approaches to combat this serious disease, aiming at reducing its impact on women’s health worldwide and improve patient outcomes. Unraveling the mysteries of circRNAs in the context of cervical cancer makes the prospects for a breakthrough in its diagnosis and treatment more promising.

Context-dependent regulation of Notch signaling in glial development and tumorigenesis.

In the mammalian brain, Notch signaling maintains the cortical stem cell pool and regulates the glial cell fate choice and differentiation. However, the function of Notch in regulating glial development and its involvement in tumorigenesis have not been well understood. Here, we show that Notch inactivation by genetic deletion of Rbpj in stem cells decreases astrocytes but increases oligodendrocytes with altered internal states. Inhibiting Notch in glial progenitors does not affect cell generation but instead accelerates the growth of Notch-deprived oligodendrocyte progenitor cells (OPCs) and OPC-related glioma. We also identified a cross-talk between oligodendrocytes and astrocytes, with premyelinating oligodendrocytes secreting BMP4, which is repressed by Notch, to up-regulate GFAP expression in adjacent astrocytes. Moreover, Notch inactivation in stem cells causes a glioma subtype shift from astroglia-associated to OPC-correlated patterns and vice versa. Our study reveals Notch's context-dependent function, promoting astrocytes and astroglia-associated glioma in stem cells and repressing OPCs and related glioma in glial progenitors.

TMIC-79. LIPOCALIN-2 MEDIATES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common primary brain tumor with a median survival of 17-20 months. Despite therapeutic treatments including surgery, radiation, chemotherapy, a population of GBM cells, termed cancer stem cells (CSCs) are radio-resistant and chemo-resistant, leading to mortality of the patient. CSCs also have altered metabolic profiles and have an enhanced capacity to scavenge nutrients from their microenvironment, including iron. Lipocalin-2 (LCN2) functions to sequester iron and is traditionally considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have both a pro and anti-tumorigenic and has context-dependent functions depending on iron status. LCN2 has been shown to be important in brain metastasis, but its role in GBM is still largely unknown. To assess a cell-intrinsic function for LNC2, we added recombinant LCN2 to low LCN2-secreting mouse GBM cell models and observed that proliferation also increased. When we knocked down LCN2 in our higher LCN2 secreting cell lines, we observed that knockdown cells had decreased viability and growth, which was not mediated by apoptosis, but rather, ferroptosis. When these cells were subsequently engrafted into wild-type mice, we observed an increase in survival. This effect was also phenocopied when the cells were implanted into LCN2 knockout mice, suggesting the tumor-intrinsic effect overpowered the global knockout model. Lastly, to investigate how LCN2 plays a role in the GBM microenvironment, we orthotopically implanted syngeneic mouse GBM cells into male and female LCN2 knockout and wild-type mice. We observed no survival difference, further suggesting that LCN2 does not function in an extrinsic manner. Taken together, these data suggest that LCN2 affects proliferation and tumorigenesis, and is another avenue to understanding the complexity of GBM biology. Strategies to reduce LCN2 in GBM may provide a therapeutic target for GBM in the future.