Search Results (374)

Wool fibre diameter is a key economic trait in wool-producing animals, and its formation is regulated by the synergistic interaction between the proliferation and differentiation of hair follicle stem cells (HFSCs) and signals from the microenvironment. Dermal papilla cells (DPCs), as a key signal source, regulate the fate of HFSCs via paracrine pathways; however, the key molecular mechanisms remain unclear. Single-cell RNA sequencing (scRNA-seq) and genome-wide association studies (GWAS) revealed that ZNF280B is specifically expressed in both DPCs and HFSCs, and its g.677G>A variant is significantly associated with wool fibre diameter. Functional studies indicate that overexpression of ZNF280B promotes the proliferation of DPCs and HFSCs and inhibits apoptosis, whilst knockdown has the opposite effect; mechanistically, ZNF280B alters mRNA levels of key marker genes of the Wnt/β-catenin signalling pathway while selectively changing transcripts of the TGF-β pathway components in DPCs, and differentially modulates key marker transcripts in both the Wnt/β-catenin and Notch pathways in HFSCs. In summary, ZNF280B mediates the paracrine signalling of DPCs to influence HFSC proliferation and differentiation. It achieves this by integrating the Wnt/β-catenin/TGF-β/Notch signalling axes. This reveals that ZNF280B acts as an important regulatory node mediating DPC-HFSC paracrine communication, and provides new insights into the developmental mechanisms of fine-wool hair follicles and molecular breeding for fibre diameter. Full article

Background/Objectives: ZNF395, also known as PBF (Human Papillomavirus Binding Factor), is an intrinsically disordered cellular protein involved in critical biological processes. These include human papillomavirus replication, the innate immune response, apoptosis induction, cell growth inhibition, the activation of autologous cytotoxic T lymphocytes, and prognosis in various cancers—all of which are associated with diseases of global significance. ZNF395 has been differentially associated with the replication of HPV8, HIV, CMV, and EBV. Notably, reports indicate contrasting behaviors across different cancer types, suggesting that it could act as a tumor suppressor or serve as a marker for poor prognosis. Furthermore, hypoxic conditions induce ZNF395 expression through the activation of HIF-1α and NF-κB, resulting in increased IL-6 and IL-8 levels in response to cellular stress, thereby promoting cell survival, migration, and angiogenesis. Methods: A non-systematic literature search was performed in PubMed (2000–2026) using keywords related to ZNF395, cancer, and viruses. Conclusions: In this work, we summarize the diverse functions performed by this single protein, challenging the traditional “one structure, one function” paradigm. Most importantly, our findings highlight that ZNF395 may hold significant potential for the diagnosis, prognosis, and treatment of cancer. Full article

Transcripts annotated as non-coding can yield both an RNA molecule and a translated product, complicating causal attribution in skeletal muscle. Three distinct claims require different evidence: a product exists, the nominated RNA generated it, and the product drives a defined phenotype. We examine them in myogenesis and regeneration using a qualitative, two-axis evidence map. The T axis records translation and RNA-of-origin evidence, whereas the F axis records experiments separating RNA-dependent from product-dependent effects for a stated model and endpoint. Endogenous coding-selective experiments support qualified product-dependent assignments for LINC00961–SPAR and MTLN/MPM. Linc-RAM/MRLN demonstrates biologically active RNA and peptide outputs, but not that both cause the same phenotype. Among the selected circRNA systems, circZNF609, circFAM188B, circNEB, and circSIK2 retain unresolved source and/or functional attribution, and none meets both T4 and F4. Rather than ranking study quality or assuming transfer across species and myogenic stages, the map identifies the experiment still needed to establish causality. Full article

Endometriosis (EMs) is a common chronic gynecological disorder characterized by the ectopic implantation and growth of endometrial-like tissue. The abnormal survival of ectopic endometrial cells, including their reduced susceptibility to apoptosis, plays an important role in the development of EMs. Cav1.3 is aberrantly upregulated in EMs and contributes to disease progression; however, the mechanism responsible for its increased expression remains unclear. In this study, protein stability and ubiquitination assays were performed in hEM15A cells. Cav1.3-interacting proteins were screened by co-immunoprecipitation coupled with liquid chromatography tandem mass spectrometry, and the regulatory pathway was further examined using in vitro experiments and animal models. We found that reduced ubiquitin–proteasome-mediated degradation increased Cav1.3 stability in hEM15A cells. Our results further showed that ZNF460 increased CRMP4 expression by activating its transcription. CRMP4 associated with Cav1.3 and reduced RNF138–Cav1.3 association, accompanied by decreased Cav1.3 ubiquitination and increased protein stability. ZNF460-dependent CRMP4 expression promoted Cav1.3 accumulation and was associated with reduced apoptosis in hEM15A cells. These findings clarify the post-translational mechanism underlying Cav1.3 upregulation in EMs and suggest that the ZNF460/CRMP4/RNF138/Cav1.3 axis may serve as a potential molecular target for EMs treatment. Full article

Kidney renal clear cell carcinoma (KIRC) is a major subtype of renal cell carcinoma with substantial molecular heterogeneity and variable clinical outcomes. Tetraspanins (TSPANs) are membrane proteins involved in cell adhesion, signaling, migration, tumor progression, and interactions with the tumor microenvironment (TME); however, their collective significance in KIRC remains insufficiently characterized. The expression profile of the TSPAN gene family was evaluated in the TCGA-KIRC cohort using GEPIA2. Differentially expressed TSPANs were further investigated through protein–protein interaction network (PPIN) and univariate survival analyses. Prognostically significant TSPANs were assessed for genomic alterations, promoter methylation, and associations with tumor-infiltrating immune cells. Feed-forward-loop (FFL) was constructed and visualized using Cytoscape. Thereafter, the findings were evaluated in an independent KIRC dataset. Several TSPANs displayed significant differential expression between KIRC and normal renal tissues. TSPAN1 and TSPAN6 were significantly associated with overall survival (OS), with higher expression corresponding to more favorable outcomes. Notably, higher TSPAN6 expression was associated with improved OS but a higher estimated risk of relapse indicating an endpoint-dependent and potentially complex prognostic relationship. Promoter methylation of TSPAN1 and TSPAN6 showed associations with selected clinicopathological characteristics, while both genes demonstrated significant relationships with specific immune-cell populations. Network analysis identified a ZNF260–miR-6794-5p–TSPAN6 FFL subnetwork motif, prioritizing TSPAN6 as the hub TSPAN. TSPAN6 was additionally detected among differentially expressed genes (DEGs) in an independent GEO cohort. This study identifies TSPAN6 as a promising candidate biomarker in KIRC and provides a multi-dimensional framework linking TSPAN dysregulation with prognosis, epigenetic regulation, immune infiltration, and regulatory networks. Experimental and clinical validation is warranted. Full article

Extrachromosomal circular DNA (eccDNA) serves as a vital regulator of gene expression and phenotypic plasticity. The Monopterus albus is a protogynous hermaphroditic fish, and the functional role of eccDNA during its female-to-male sex reversal remains poorly understood. We conducted Circle-seq analysis on gonadal tissues of super-female and male individuals and integrated our findings with previously published gonadal RNA-seq data. A total of 62,574 and 34,562 eccDNAs were, on average, identified in the two groups, and 7881 down-regulated and 2738 up-regulated differentially abundant eccDNAs were screened in male gonads. Three candidate eccDNAs, eccDNA^Dmrt1a, eccDNA^Sox9a1 and eccDNA^ZNF239, were selected for subsequent analysis. Quantitative real-time PCR was applied to detect the overall transcriptional levels of their corresponding host genes, covering transcripts derived from both genomic DNA and eccDNA. Spatiotemporal expression profiling and letrozole induction experiments revealed male-biased expression of Dmrt1a and Sox9a1, while ZNF239 was predominantly expressed in female gonads. Complete sex reversal was observed in female M. albus after 90-day letrozole treatment, accompanied by elevated Dmrt1a/Sox9a1 and reduced ZNF239 transcription. Fluorescence in situ hybridization localized these transcripts in gonadal germ cells and somatic cells across developmental stages. This study verifies the production of eccDNA during gonadal development. The results indicate that Dmrt1a and Sox9a1 may facilitate sex reversal and suggest that ZNF239 is likely involved in ovarian development. This work provides novel clues for deciphering the molecular mechanism underlying sex reversal from the eccDNA perspective. Full article

Sebaceous carcinoma is an uncommon but potentially aggressive adnexal malignancy whose molecular pathogenesis has been substantially clarified in recent years. Rather than representing a single molecular entity, sebaceous carcinoma is now understood as a biologically heterogeneous group of tumors arising through distinct yet sometimes overlapping oncogenic pathways. Recent genomic and multi-omics studies have identified several major molecular subsets, including mismatch repair-deficient (dMMR)/microsatellite instability (MSI)-associated tumors, ultraviolet (UV) radiation-driven tumors, and pauci-mutational tumors characterized predominantly by alterations in cell-cycle and epithelial differentiation regulators such as TP53, RB1, and ZNF750. These findings have also reinforced biologically relevant differences between ocular and extraocular sebaceous carcinoma, with periocular tumors more often enriched for TP53/RB1/ZNF750-driven mechanisms and extraocular tumors more frequently showing UV-related and dMMR signatures. In addition to these core pathways, recent evidence has highlighted the contribution of NOTCH signaling, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway alterations, copy-number changes including MYC amplification, rare human papillomavirus (HPV)-associated cases, and emerging transcriptomic abnormalities involving cholesterol metabolism and sebaceous differentiation programs. These advances not only deepen current understanding of sebaceous carcinoma biology but also have important diagnostic, prognostic, and therapeutic implications, particularly in relation to Lynch/Muir–Torre syndrome screening, molecular subclassification, and the potential use of immune checkpoint inhibitors and other targeted strategies in selected patients. This review provides an updated overview of the molecular pathogenesis of sebaceous carcinoma, focusing on the main genomic, transcriptomic, and biologically actionable alterations described to date, and discusses their implications for tumor classification, pathogenesis, and future translational research. Full article

During protein synthesis, ribosome stalling, collision, and aberrant elongation can lead to the accumulation of defective nascent polypeptides and compromise cellular homeostasis. To counteract such translational disturbances, eukaryotic cells have evolved a highly conserved translational quality control network, in which the ribosome-associated quality control (RQC) pathway plays a central role in the recognition and elimination of aberrant translation complexes. Zinc Finger Protein 598 (ZNF598), a key E3 ubiquitin ligase in mammalian cells, functions as an essential factor in the early recognition and signal transduction steps of the RQC pathway. Accumulating evidence indicates that ZNF598 senses aberrant translational states, and particularly in the context of ribosome collision, mediates site-specific ubiquitination of 40S ribosomal proteins, thereby promoting ribosome splitting, nascent chain clearance, and subsequent processing of defective mRNAs. Beyond its canonical role in RQC, ZNF598 has also been implicated in the translational repression of defective mRNAs, regulation of inflammatory signaling, antiviral responses, and control of toxic translation products associated with neurodegenerative disorders. In this review, we summarize the structural features, molecular mechanisms, regulatory networks, and physiological as well as pathological functions of ZNF598. We also discuss current controversies and future directions in the field, with the aim of providing a broader framework for understanding translational quality control and its therapeutic potential. Full article

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, immune suppression, lipid metabolism, and tissue repair. In particular, Zinc finger protein 750 (ZNF750), grainyhead-like transcription factor 3 (GRHL3), and ovo-like transcriptional repressor 1 (OVOL1) integrate epidermal differentiation with the suppression of inflammatory signaling by regulating lipid metabolism, innate immune sensors, stress-response pathways, and environmentally responsive transcriptional programs. Disruption of these regulatory nodes impairs barrier integrity, amplifies inflammatory signaling, and predisposes to chronic skin diseases, including psoriasis and atopic dermatitis. Full article

Background: Pathogenic variants in ZNF292 cause intellectual disability type 64 (MIM#619188), characterized by intellectual impairment ranging from mild to severe, speech delay, and autism spectrum disorder. However, reports of ZNF292-related neurodevelopmental disorders remain scarce, and most published studies are based on multi-center cohorts. Methods: We performed whole-exome sequencing in eight unrelated individuals presenting with unexplained neurodevelopmental disorders, including global developmental delay and/or intellectual disability. Detailed clinical characterization, neuroimaging, and developmental assessments were conducted. Results: Seven de novo variants in ZNF292 were identified, including two nonsense and five frameshift variants, namely, c.4189C>T (p.Arg1397Ter), c.6343C>T (p.Arg2115Ter), c.1533del (p.Ile511Metfs*11), c.3094dup (p.Ser1032Phefs*18), c.3997_3998del (p.Thr1333Glnfs*8), c.6028_6031del (p.Ala2010Ter) and c.6160_6161del (p.Glu2054Lysfs*14). Among these, c.1533del (p.Ile511Metfs11), c.3094dup (p.Ser1032Phefs18) and c.3997_3998del (p.Thr1333Glnfs*8) are reported here for the first time. All variants were classified as pathogenic. All individuals exhibited global developmental delay, intellectual disability, and short stature. The majority presented with language impairment, motor delays, autism spectrum features, and dysmorphic facial features, while brain magnetic resonance imaging revealed nonspecific abnormalities such as ventriculomegaly. Conclusions: This study contributes additional cases to the expanding phenotypic and mutational spectrum of ZNF292-related neurodevelopmental disorder. Growth retardation was observed in all eight individuals, but given the limitations of a single-center referral cohort, this observation should be interpreted with caution and requires validation in larger studies. Full article

Skeletal muscle is a continuously load-bearing tissue whose growth, repair, and age-related decline are governed by mechanical signals; failure of this mechano-regulation underlies disuse atrophy and sarcopenia. Piezo1, a mechanically activated cation channel, has emerged as a tractable transducer of these signals in muscle, contributing to satellite-cell quiescence and senescence, regenerative division, myoblast fusion, and the response to loading and unloading. In parallel, the myogenic noncoding RNA program is among the best defined in any lineage, with myomiRs miR-1/133/206, the long noncoding RNA LINC-MD1, and the circular RNA circ-ZNF609 being established regulators of the proliferation-to-differentiation transition. These layers are linked because Piezo1-evoked calcium influx feeds the RhoA/ROCK-actin-MRTFA-SRF and YAP/TAZ axis that drives myogenic transcription, yet no direct coupling between Piezo1 and noncoding RNAs has been demonstrated in skeletal myocytes. Drawing on validated precedents from vascular, cardiac, and tendon tissues, this review consolidates the two pillars, frames their convergence as a testable question, distinguishes validated relationships from hypotheses, and proposes three falsifiable predictions using an unbiased candidate selection strategy. The contribution of this review is this testable framework rather than any specific candidate list. Mechanically tunable noncoding RNAs may thus represent an underexplored node for counteracting disuse atrophy and sarcopenia. Full article

Enhancers regulate genes over long genomic distances by physically looping to interact with promoters, a process highly dependent on specific protein recruitment and local histone modifications. We identified 1399, 1394, and 4063 enhancer-associated chromatin loops in GM12878, K562, and HepG2 cell lines, respectively, and found that dual-function proteins, characterized by both activating and repressing activities, preferentially localized at loop-anchored enhancers. Although protein co-localization patterns varied among cell types, CTCF, RAD21, SMC3, and ZNF143 consistently co-localized with one another at these enhancers. Furthermore, enhancer-associated loops localized primarily to the A compartment. Enhancers anchored in A-A loops showed greater enrichment of H3K4me1, H3K4me2, H3K9ac, and H3K27ac than those anchored in B-B loops. However, in K562 cells, enhancers anchored in B-B loops exhibited minor changes in active histone modification enrichment compared to their A-A counterparts, and even showed higher proportions of H3K4me2 and H3K9ac enrichment for enhancer–promoter loops. Nevertheless, across all three cell lines, A-A enhancer–promoter loops with both active anchors exhibited significantly higher target gene expression than other A-A loops and B-B loops. Our study suggests that enhancer-associated loop formation correlates with dual-function protein co-localization and active histone modification enrichment, which may collectively contribute to target gene transcription. Full article

Heat stress limits dairy production. The temperature-humidity index (THI), combining temperature and relative humidity, is widely used to assess heat stress. However, in Chinese Holstein cattle, the phenotypic responses of milk traits and genotype-environment interaction mechanisms under different THI conditions are understudied. Based on 63,334 records from 7240 cows (milk yield, fat percentage, protein percentage), matched with meteorological data and 113,297 SNPs, we employed a random-effects GWAS to examine SNP effects across a continuous THI gradient, comparing results with conventional, temperature-, and humidity-interaction GWAS. As THI increased, all traits declined with distinct patterns. Random regression GWAS identified 149 significant SNP × THI interactions (5 for MY, 86 for FP, 58 for PP), distributed across BTA5, BTA6, BTA14, and BTA20. Candidate gene annotation identified 52 candidate genes near significant SNPs, of which 50 core candidate genes were supported in both temperature and humidity GWAS. The most robustly supported core candidate genes include DGAT1, CPSF1, ABCG2, MGST1, VPS28, PPP1R16A, ZNF250, GRID2, KCNC2, and LOC787350—of which DGAT1, ABCG2, and MGST1 have been functionally validated in milk production traits, whereas others represent novel candidates requiring further investigation. Temperature and THI-GWAS showed high consistency, while humidity-GWAS detected both overlapping and specific signals. Incorporating THI as a continuous environmental gradient identifies environment-dependent regulatory signals not captured by conventional GWAS, providing candidate genes that may contribute to future breeding strategies after further validation. Full article

Aqueous zinc metal batteries are promising for safe and cost-effective energy storage. However, their practical application is limited by the intrinsic instability of the Zn/electrolyte interface, including water-induced hydrogen evolution, Zn corrosion, and dendrite-prone Zn deposition. Herein, glutaronitrile (GLN) is introduced as a multifunctional dinitrile additive to stabilize Zn metal anodes through coupled regulation of solvation chemistry and interfacial evolution. The polar C≡N groups of GLN can coordinate with Zn²⁺, to replace part of the water molecules in the primary solvation shell, thereby suppressing the activity of coordinated water. Meanwhile, uncoordinated C≡N groups act as hydrogen-bond acceptors to reorganize the surrounding water network, further suppressing free-water participation in hydrogen evolution and corrosion. This dual regulation optimizes the Zn/electrolyte interfacial environment, improves electrolyte wettability on Zn, homogenizes Zn²⁺ flux, and promotes compact, dendrite-suppressed Zn deposition. Additionally, GLN promotes the formation of a chemically heterogeneous interfacial structure enriched with ZnF₂ in the inner region, which further protects the Zn surface and stabilizes the Zn plating/stripping process. The optimized ZHG6 electrolyte enables Zn||Zn symmetric cells to cycle stably for over 900 h at 1 mA cm⁻² and 1 mAh cm⁻², while Zn||Cu cells maintain high Coulombic efficiency during long-term cycling. Furthermore, Zn||V₆O₁₃ full cells exhibit enhanced cycling stability and rate capability, achieving stable operation for 3200 cycles at 5 A g⁻¹. As evidenced in this work, dinitrile-based molecular additives provide an effective and scalable strategy to fabricate durable aqueous zinc metal batteries. Full article

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder with a well- documented prodromal phase during which non-motor symptoms appear years before motor onset. Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that is significantly more prevalent in PD patients than in the general population. The biological mechanisms underlying this association have not been integrated into a single framework. Objectives: This narrative review aims to synthesise the available evidence on the molecular, genetic, and pathophysiological mechanisms linking SD and PD. Methods: A literature search was conducted across PubMed/MEDLINE, Scopus and ScienceDirect, supplemented by manual searches in OMIM and GeneCards. Results: Four major biological links between SD and PD have been proposed. First, alpha-synuclein deposits are detectable in cutaneous nerve fibres and autonomic fibres innervating sebaceous glands in PD patients and their pattern has been associated with disease subtype and progression. Second, dysfunction in ceramide and sphingolipid metabolism, associated with variants in GBA1, LRRK2, and ZNF750, has been linked to impaired lysosomal function and skin barrier integrity in both brain and skin tissue. Third, Malassezia, a commonly associated organism and possible trigger in susceptible hosts, produces metabolites that activate neuroinflammatory pathways relevant to PD and PD patients show altered Malassezia species composition on their skin. Fourth, NLRP3 inflammasome activation, which can be triggered by ceramide accumulation and fungal metabolites, has been proposed as a shared inflammatory mechanism that may operate in both keratinocytes and dopaminergic neurons. Conclusions: SD and PD appear to share overlapping genetic, lipidomic, microbial, and neuroinflammatory features. These associations are consistent with, but do not yet prove, a common pathological basis rather than a coincidental one. SD may therefore represent a potential prodromal feature or risk marker of PD. Future research should examine whether targeted intervention in high-risk SD patients can delay or modify PD onset. Full article