Regulatory Feedback Loop Research Articles

General relationship of local topologies, global dynamics, and bifurcation in cellular networks

Cellular networks realize their functions by integrating intricate information embedded within local structures such as regulatory paths and feedback loops. However, the precise mechanisms of how local topologies determine global network dynamics and induce bifurcations remain unidentified. A critical step in unraveling the integration is to identify the governing principles, which underlie the mechanisms of information flow. Here, we develop the cumulative linearized approximation (CLA) algorithm to address this issue. Based on perturbation analysis and network decomposition, we theoretically demonstrate how perturbations affect the equilibrium variations through the integration of all regulatory paths and how stability of the equilibria is determined by distinct feedback loops. Two illustrative examples, i.e., a three-variable bistable system and a more intricate epithelial-mesenchymal transition (EMT) network, are chosen to validate the feasibility of this approach. These results establish a solid foundation for understanding information flow across cellular networks, highlighting the critical roles of local topologies in determining global network dynamics and the emergence of bifurcations within these networks. This work introduces a novel framework for investigating the general relationship between local topologies and global dynamics of cellular networks under perturbations.

Arabidopsis B-BOX DOMAIN PROTEIN14/15/16 form a feedback loop with ELONGATED HYPOCOTYL 5 and PHYTOCHROME-INTERACTING FACTORs to regulate hypocotyl elongation

Light-regulated developmental processes such as photomorphogenesis and flowering play important roles in the plant life cycle, from seedling emergence to reproduction. Three members of the Arabidopsis thaliana B-BOX DOMAIN PROTEIN (BBX) family, BBX14, BBX15, and BBX16 (hereafter BBX14/15/16), redundantly regulate flowering time, but whether this genetic redundancy also affects the regulation of photomorphogenesis remains unclear. Here, we show that light induces BBX14/15/16 expression primarily in the hypocotyl, where BBX14/15/16 redundantly repress hypocotyl elongation. PHYTOCHROME-INTERACTING FACTORs (PIFs) negatively regulate BBX14/15/16 expression mainly through GOLDEN-LIKE proteins (GLKs); however, analyses of ChIP-seq data showed that PIFs are recruited to the BBX14/15/16 loci and can also regulate these genes independently of GLKs. ELONGATED HYPOCOTYL 5 (HY5), a major regulator of photomorphogenesis, also directly binds to the BBX14/15/16 loci and regulates their expression. Simultaneous knockdown of BBX14/15/16 resulted in significant downregulation of HY5 and upregulation of PIFs, suggesting that these factors participate in a feedback regulatory loop. Indeed, BBX14/15/16 induced HY5 promoter activity by binding to the HY5 promoter. The brassinosteroid-responsive gene TOUCH4 (TCH4) and several auxin-responsive SMALL AUXIN UPREGULATED RNA (SAUR) genes were upregulated in the BBX14/15/16 knockdown plants, suggesting that auxin and brassinosteroids might participate in BBX14/15/16-mediated hypocotyl regulation. Mutating the predicted BBX-binding sites in SAUR4 and TCH4 impaired their regulation by BBX14/15/16. We propose that BBX14/15/16, together with HY5 and PIFs, form a feedback loop that regulates the expression of auxin- and brassinosteroid-related genes to modulate hypocotyl elongation.

Sulfur metabolism under stress: Oxidized glutathione inhibits methionine biosynthesis by destabilizing the enzyme cystathionine γ-synthase.

Cysteine is the precursor for the biosynthesis of glutathione, a key stress-protective metabolite, and methionine, which is imperative for cell growth and protein synthesis. The exact mechanism that governs the routing of cysteine toward glutathione or methionine during stresses remains unclear. Our study reveals that under oxidative stress, methionine and glutathione compete for cysteine and that the increased oxidized glutathione (GSSG) levels under stress hinder methionine biosynthesis. Moreover, we find that inhibition occurs as GSSG binds to and accelerates the degradation of cystathionine γ-synthase, a key enzyme in the methionine synthesis pathway. Consequently, this leads to a reduction in the flux toward methionine-derived metabolites and redirects cysteine utilization toward glutathione, thereby enhancing plant protection. Our study suggests a novel regulatory feedback loop involving glutathione, methionine, and cysteine, shedding light on the plant stress response and the adaptive rerouting of cysteine. These findings offer new insights into the intricate balance of growth and protection in plants and its impact on their nutritional value due to low methionine levels under stress.

AP1c and SOC1 Form a Regulatory Feedback Loop to Regulate Flowering Time in Soybean.

Flowering time is a key agronomic trait that directly affects soybean yield. Both APETALA1 (AP1) and SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) regulate flowering time in soybean, but their genetic and regulatory relationships have not been clarified. Here, we report that AP1c physically interacted with two SOC1 proteins, SOC1a and SOC1b, and that these SOC1s upregulated the expression of AP1c, promoting flowering. Moreover, AP1c repressed the expression of the SOC1s by directly binding to their promoters, thus preventing plants from flowering too early. These findings indicate that AP1c and SOC1s form a regulatory feedback loop that regulates flowering time. Importantly, we identified an exceptional allele, AP1cG, that was selected for during soybean domestication and promotes the early-flowering phenotype in cultivated soybean. Collectively, our work identifies a previously unknown allelic combination potentially useful for both classical and molecular soybean breeding.

LINC01116-dependent upregulation of RNA polymerase I transcription drives oncogenic phenotypes in lung adenocarcinoma

BackgroundHyperactive RNA Polymerase I (Pol I) transcription is canonical in cancer, associated with malignant proliferation, poor prognosis, epithelial-mesenchymal transition, and chemotherapy resistance. Despite its significance, the molecular mechanisms underlying Pol I hyperactivity remain unclear. This study aims to elucidate the role of long noncoding RNAs (lncRNAs) in regulating Pol I transcription in lung adenocarcinoma (LUAD).MethodsBioinformatics analyses were applied to identify lncRNAs interacting with Pol I transcriptional machinery. Fluorescence in situ hybridization was employed to examine the nucleolar localization of candidate lncRNA in LUAD cells. RNA immunoprecipitation assay validated the interaction between candidate lncRNA and Pol I components. Chromatin isolation by RNA purification and Chromatin Immunoprecipitation (ChIP) were utilized to confirm the interactions of candidate lncRNA with Pol I transcriptional machinery and the rDNA core promoter. Functional analyses, including lncRNA knock-in and knockdown, inhibition of Pol I transcription, quantitative PCR, cell proliferation, clonogenicity, apoptosis, cell cycle, wound-healing, and invasion assays, were performed to determine the effect of candidate lncRNA on Pol I transcription and associated malignant phenotypes in LUAD cells. ChIP assays and luminometry were used to investigate the transcriptional regulation of the candidate lncRNA.ResultsWe demonstrate that oncogenic LINC01116 scaffolds essential Pol I transcription factors TAF1A and TAF1D, to the ribosomal DNA promoter, and upregulate Pol I transcription. Crucially, LINC01116-driven Pol I transcription activation is essential for its oncogenic activities. Inhibition of Pol I transcription abrogated LINC01116-induced oncogenic phenotypes, including increased proliferation, cell cycle progression, clonogenicity, reduced apoptosis, increased migration and invasion, and drug sensitivity. Conversely, LINC01116 knockdown reversed these effects. Additionally, we show that LINC01116 upregulation in LUAD is driven by the oncogene c-Myc, a known Pol I transcription activator, indicating a functional regulatory feedback loop within the c-Myc-LINC01116-Pol I transcription axis.ConclusionCollectively, our findings reveal, for the first time, that LINC01116 enhances Pol I transcription by scaffolding essential transcription factors to the ribosomal DNA promoter, thereby driving oncogenic activities in LUAD. We propose the c-Myc-LINC01116-Pol I axis as a critical oncogenic pathway and a potential therapeutic target for modulating Pol I transcription in LUAD.Graphical

Characterisation of APOBEC3B-Mediated RNA editing in breast cancer cells reveals regulatory roles of NEAT1 and MALAT1 lncRNAs

RNA editing is a crucial post-transcriptional process that influences gene expression and increases the diversity of the proteome as a result of amino acid substitution. Recently, the APOBEC3 family has emerged as a significant player in this mechanism, with APOBEC3A (A3A) having prominent roles in base editing during immune and stress responses. APOBEC3B (A3B), another family member, has gained attention for its potential role in generating genomic DNA mutations in breast cancer. In this study, we coupled an inducible expression cell model with a novel methodology for identifying differential variants in RNA (DVRs) to map A3B-mediated RNA editing sites in a breast cancer cell model. Our findings indicate that A3B engages in selective RNA editing including targeting NEAT1 and MALAT1 long non-coding RNAs that are often highly expressed in tumour cells. Notably, the binding of these RNAs sequesters A3B and suppresses global A3B activity against RNA and DNA. Release of A3B from NEAT1/MALAT1 resulted in increased A3B activity at the expense of A3A activity suggesting a regulatory feedback loop between the two family members. This research substantially advances our understanding of A3B’s role in RNA editing, its mechanistic underpinnings, and its potential relevance in the pathogenesis of breast cancer.

Can stable introns and noncoding RNAs be harnessed to improve health through activation of mitohormesis?

Ever since their introduction a decade ago, stable introns, a type of noncoding (nc)RNAs, are found to be key players in different important cellular processes acting through regulation of gene expression and feedback loops to maintain cellular homeostasis. Despite being commonly regarded as useless byproducts, recent studies in yeast suggested that stable introns are essential for cell survivability under starvation. In Drosophila, we found that a stable intron, sisR-1, has a direct effect in regulating mitochondrial dynamics during short-term fasting and subsequently improved overall oocyte quality. We speculated that the beneficial effects implicated by sisR-1 is through the activation of mitohormesis, an interesting phenomenon in mitochondrial biology. Mitohormesis is suggested to improve health span and lifespan of cells and organisms, but the involvement of ncRNAs is not well-documented. Here, we discuss the potential role of sisR-1 and other ncRNAs in activating mitohormesis and the possible applications in improving cellular and organismal health.

VvMYBA1 and VvMYB3 form an activator–repressor system to regulate anthocyanin biosynthesis in grape

Anthocyanins are important metabolites that provide a red or blue–purple hue to plants. The biosynthesis of these metabolites is mainly activated by the MYB-bHLH-WD40 (MBW) complex and repressed by a wide variety of proteins. Studies have shown that MYB activators activate MYB repressors to balance anthocyanin biosynthesis. However, there is a scarcity of studies investigating this mechanism in grapes. To explore the transcription factors involved in the regulation of anthocyanin biosynthesis, we reanalyzed the RNA-seq database for different developmental stages of ‘Muscat Hamburg’ berries, and the R2R3-MYB gene, annotated as VvMYB3, was screened. Our study revealed the anthocyanin content of the grape cultivar ‘Y73’ was higher than that of its parental cultivar MH, and the putative repressor VvMYB3 was found to be highly expressed in ‘Y73’ by qRT-PCR. The calli transgenic assays demonstrated that the repressive activity of VvMYB3 was conferred by the bHLH-binding motif, as well as by the C1 and C2 motifs. Yeast hybridization and chip-PCR assays revealed that VvMYB3 could repress anthocyanin biosynthesis by competing with VvMYBA1 to bind to VvMYC1 and promoting histone deacetylation of VvUFGT via the C2 motif. However, the expression of VvMYB3 was activated by VvMYBA1, which forms a negative feedback regulatory loop to modulate anthocyanin accumulation. In addition, we found a 408-bp repeat tandem sequence insertion in the VvMYBA1 promoter region of ‘Y73’ by sequencing. The GUS activity analysis showed that this sequence enhanced the expression of VvMYBA1 and led to an excessive accumulation of anthocyanins. Overall, our results provide insights into the anthocyanin activator–repressor system in grapes that prevents overaccumulation of anthocyanins.

Super-Enhancer Driven LIF/LIFR-STAT3-SOX2 Regulatory Feedback Loop Promotes Cancer Stemness in Head and Neck Squamous Cell Carcinoma.

Super-enhancers (SEs) have been recognized as key epigenetic regulators underlying cancer stemness and malignant traits by aberrant transcriptional control and promising therapeutic targets against human cancers. However, the SE landscape and their roles during head and neck squamous cell carcinoma (HNSCC) development especially in cancer stem cells (CSCs) maintenance remain underexplored yet. Here, we identify leukemia inhibitory factor (LIF)-SE as a representative oncogenic SE to activate LIF transcription in HNSCC. LIF secreted from cancer cells and cancer-associated fibroblasts promotes cancer stemness by driving SOX2 transcription in an autocrine/paracrine manner, respectively. Mechanistically, enhancer elements E1, 2, 4 within LIF-SE recruit SOX2/SMAD3/BRD4/EP300 to facilitate LIF transcription; LIF activates downstream LIFR-STAT3 signaling to drive SOX2 transcription, thus forming a previously unknown regulatory feedback loop (LIF-SE-LIF/LIFR-STAT3-SOX2) to maintain LIF overexpression and CSCs stemness. Clinically, increased LIF abundance in clinical samples correlate with malignant clinicopathological features and patient prognosis; higher LIF concentrations in presurgical plasma dramatically diminish following cancer eradication. Therapeutically, pharmacological targeting LIF-SE-LIF/LIFR-STAT3 significantly impairs tumor growth and reduces CSC subpopulations in xenograft and PDX models. Our findings reveal a hitherto uncharacterized LIF-SE-mediated auto-regulatory loop in regulating HNSCC stemness and highlight LIF as a novel noninvasive biomarker and potential therapeutic target for HNSCC.

Piperonyl butoxide elicits a robust transcriptional response in adult Drosophila melanogaster

While much attention has been devoted to understanding the transcriptional changes underlying resistance to insecticides, comparatively little is known about the transcriptional response of naive insects to agrochemicals. In this study, we analyze the transcriptomic response of an insecticide susceptible strain of Drosophila melanogaster to nine agrochemicals using a robust method that goes beyond classical replication standards. Our findings demonstrate that exposure to piperonyl butoxide (PBO), but not to eight other compounds, elicits a robust transcriptional response in a wild-type strain of Drosophila melanogaster. PBO exposure leads to the upregulation of a subset of Cyps, GSTs, UGTs and EcKls. This response is both time and concentration-dependent, suggesting that the degree of inhibition of P450 activity correlates with the magnitude of the transcriptional response. Furthermore, the upregulation of these enzymes is excluded from reproductive organs. Additionally, different sets of genes are regulated in the digestive/secretory tract and the carcass. Our results suggest that P450s play a role in metabolizing yet unidentified endogenous compounds and are involved in an as-yet-unknown physiological regulatory feedback loop.

The abscisic acid-responsive transcriptional regulatory module CsERF110–CsERF53 orchestrates citrus fruit coloration

Carotenoid biosynthesis is closely associated with abscisic acid (ABA) during the ripening process of non-climacteric fruits, but the regulatory mechanism that links ABA signaling to carotenoid metabolism remains largely unclear. Here, we identified two master regulators of ABA-mediated citrus fruit coloration, CsERF110 and CsERF53, which activate the expression of carotenoid metabolism genes (CsGGPPS, CsPSY, CsPDS, CsCRTISO, CsLCYB2, CsLCYE, CsHYD, CsZEP, and CsNCED2) to facilitate carotenoid accumulation. Further investigations showed that CsERF110 not only activates the expression of CsERF53 by binding to its promoter but also interacts with CsERF53 to form the transcriptional regulatory module CsERF110–CsERF53. We also discovered a positive feedback regulatory loop between the ABA signal and carotenoid metabolism regulated by the transcriptional regulatory module CsERF110–CsERF53. Our results reveal that the CsERF110–CsERF53 module responds to ABA signaling, thereby orchestrating citrus fruit coloration. Considering the importance of carotenoid content for citrus and many other carotenoid-rich crops, the revelation of molecular mechanisms that underlie ABA-mediated carotenoid biosynthesis in plants will facilitate the development of transgenic/gene-editing approaches, further contributing to improving the quality of citrus and other carotenoid-rich crops.

Engineered targeting OIP5 sensitizes bladder cancer to chemotherapy resistance via TRIP12-PPP1CB-YBX1 axis.

Chemoresistance is an important cause of treatment failure in bladder cancer, and identifying genes that confer drug resistance is an important step toward developing new therapeutic strategies to improve treatment outcomes. In the present study, we show that gemcitabine plus cisplatin (GEM/DDP) therapy induces NF-κB signaling, which promotes p65-mediated transcriptional activation of OIP5. OIP5 recruits the E3 ubiquitin ligase TRIP12 to bind to and degrade the phosphatase PPP1CB, thereby enhancing the transcription factor activity of YBX1. This in turn upregulates drug-resistance-related genes under the transcriptional control of YBX1, leading to chemoresistance. Moreover, PPP1CB degradation can enhance the phosphorylation activity of IKKβ, triggering the NF-κB signaling cascade, which further stimulates OIP5 gene expression, thus forming a negative feedback regulatory loop. Consistently, elevated OIP5 expression was associated with chemoresistance and poor prognosis in patients with bladder cancer. Furthermore, we used a CRISPR/Cas9-based engineered gene circuit, which can monitor the progression of chemoresistance in real-time, to induce OIP5 knockout upon detection of increased NF-κB signaling. The gene circuit significantly inhibited tumor cell growth in vivo, underscoring the potential for synergy between gene therapy and chemotherapy in the treatment of cancer.

PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells.

Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6 hi stem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cells in vivo . The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.

Regulation of immune cells by miR-451 and its potential as a biomarker in immune-related disorders: a mini review.

In 2005, Altuvia and colleagues were the first to identify the gene that encodes miR-451 in the human pituitary gland, located in chromosome region 17q11.2. Subsequent studies have confirmed that miR-451 regulates various immune cells, including T cells, B cells, microglia, macrophages, and neutrophils, thereby influencing disease progression. The range of immune-related diseases affected encompasses various cancers, lymphoblastic leukemia, and injuries to the lungs and spinal cord, among others. Moreover, miR-451 is produced by immune cells and can regulate both their own functions and those of other immune cells, thus creating a regulatory feedback loop. This article aims to comprehensively review the interactions between miR-451 and immune cells, clarify the regulatory roles of miR-451 within the immune system, and assess its potential as both a therapeutic target and a biomarker for immune-related diseases.

Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation

Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.

Circ6834 suppresses non-small cell lung cancer progression by destabilizing ANHAK and regulating miR-873-5p/TXNIP axis

BackgroundCircular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear.MethodsIn this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments.ResultsOur results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells.ConclusionIn conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.

Understanding the molecular mechanisms of drought tolerance in wild soybean (Glycine soja) through multi-omics-based alternative splicing predictions

The absence of adequate moisture resulting from drought poses a significant threat to both the viability and productivity of soybean cultivation. Genetic variation in common soybeans has been noticeably reduced through continuous breeding, and wild relatives with wider genetic diversity are one of the best tools in the search for new tolerance genes. In this study, we selected 139 genes co-expressed at transcript and protein levels in response to drought in Glycine soja through a multi-omics analysis. Drought stress induced co-expression of transcripts and proteins involved in dopamine synthesis within tyrosine metabolism. Polyphenol oxidase, involved in the dopamine synthesis process, was uniquely identified in both DEGs and DEPs, with its protein abundance increased. Co-expression of 9-lipoxygenase during linoleic acid metabolism was confirmed, along with consistent protein accumulation. The co-expression profiling of transcripts and proteins suggests that they may influence their regulatory feedback loops or unknown regulatory mechanisms. Additionally, we predicted the regulation of alternative splicing (AS) in response to drought. AS was predicted for 139 co-expressed genes, and four drought-tolerance-related gene candidate groups were selected. The expression levels of four genes, FT1, CCR1L, RPL18, and uncharacterized LOC114422617, varied depending on their transcript isoforms under drought stress. The occurrence of AS under drought stress may play a role in eliminating susceptibility genes or inducing tolerance genes to adapt to drought stress. Overall, this study reveals a novel mechanism of drought adaptation in wild soybean by predicting the regulation of metabolic pathways and AS events at the transcriptome and proteome levels and presents potential targets for soybean breeding.

Heterogeneous identity, stiffness and growth characterise the shoot apex of Arabidopsis stem cell mutants.

Stem cell homeostasis in the shoot apical meristem involves a core regulatory feedback loop between the signalling peptide CLAVATA3, produced in stem cells, and the transcription factor WUSCHEL, expressed in the underlying organising centre. clavata mutant meristems display massive overgrowth, which is thought to be caused by stem cell overproliferation, although it is unknown how uncontrolled stem cell divisions lead to this altered morphology. Here we reveal local buckling defects in mutant meristems, and use analytical models to show how mechanical properties and growth rates may contribute to the phenotype. Indeed, clavata meristems are mechanically more heterogeneous than the wild type, and also display regional growth heterogeneities. Furthermore, stereotypical wild-type meristem organisation is lost in mutants, in which cells simultaneously express distinct fate markers. Finally, cells in mutant meristems are auxin responsive, suggesting that they are functionally distinguishable from wild-type stem cells. Thus all benchmarks show that clavata meristem cells are different from wild-type stem cells, suggesting that overgrowth is caused by the disruption of a more complex regulatory framework that maintains distinct genetic and functional domains in the meristem.

Regulatory feedback loop between circ-EIF4A3 and EIF4A3 Enhances autophagy and growth in colorectal cancer cells

Recent studies indicate that circular RNAs (circRNAs) are crucial in the progression of colorectal cancer (CRC). Eukaryotic translation initiation factor 4A3 (EIF4A3) has been identified as a promoter of circRNA production. The biological roles and mechanisms of EIF4A3-derived circRNA (circEIF4A3) in CRC cell autophagy remain poorly understood. This study explores the effects of circEIF4A3 on CRC cell growth and autophagy, aiming to elucidate the underlying molecular mechanisms. We discovered that EIF4A3 and circEIF4A3 synergistically enhance CRC cell growth. CircEIF4A3 sequesters miR-3126–5p, consequently upregulating EIF4A3. Further, circEIF4A3 increases EIF4A3 expression, which promotes autophagy by stabilizing ATG5 mRNA and enhances ATG7 protein stability through the stabilization of USP14 mRNA, a deubiquitinating enzyme. Upregulation of ATG5 and ATG7 counteracts the growth-inhibitory effects of EIF4A3 knockdown on CRC cells. Moreover, our findings demonstrate that EIF4A3 induces the formation of circEIF4A3 in CRC cells. In conclusion, a positive feedback loop between circEIF4A3 and EIF4A3 supports CRC cell growth by facilitating autophagy.

A Negative Regulatory Feedback Loop within the JAK-STAT Pathway Mediated by the Protein Tyrosine Phosphatase DUSP14 in Shrimp.

The JAK-STAT pathway is a central communication node for various biological processes. Its activation is characterized by phosphorylation and nuclear translocation of the transcription factor STAT. The regulatory balance of JAK-STAT signaling is important for maintenance of immune homeostasis. Protein tyrosine phosphatases (PTPs) induce dephosphorylation of tyrosine residues in intracellular proteins and generally function as negative regulators in cell signaling. However, the roles of PTPs in JAK-STAT signaling, especially in invertebrates, remain largely unknown. Pacific white shrimp Penaeus vannamei is currently an important model for studying invertebrate immunity. This study identified a novel member of the dual-specificity phosphatase (DUSP) subclass of the PTP superfamily in P. vannamei, named PvDUSP14. By interacting with and dephosphorylating STAT, PvDUSP14 inhibits the excessive activation of the JAK-STAT pathway, and silencing of PvDUSP14 significantly enhances humoral and cellular immunity in shrimp. The promoter of PvDUSP14 contains a STAT-binding motif and can be directly activated by STAT, suggesting that PvDUSP14 is a regulatory target gene of the JAK-STAT pathway and mediates a negative feedback regulatory loop. This feedback loop plays a role in maintaining homeostasis of JAK-STAT signaling and is involved in antibacterial and antiviral immune responses in shrimp. Therefore, the current study revealed a novel inhibitory mechanism of JAK-STAT signaling, which is of significance for studying the regulatory mechanisms of immune homeostasis in invertebrates.