Cell and Bioscience最新文献

Background: Both obesity and DNA methylation (DNAm) are influenced by genetic factors. Despite more than a thousand of obesity-related DNAm sites (CpGs) being identified, studies that account for genetic influences in these associations are limited.

Results: Using data from 1,074 twins in the Chinese National Twin Registry and bivariate structural equation models (SEMs), we investigated the phenotypic (Rph), genetic (Ra), and environmental (Re) correlations between genome-wide DNAm and three obesity indices: BMI, waist circumference (WC), and waist-to-hip ratio (WHR). Genome-wide, correlations between DNAm and obesity were small (Rph = 0.04, Ra = 0.08-0.09, Re = 0.02-0.03). For CpGs with high phenotypic correlation (Rph > 0.1), the mean genetic and environmental correlations were 0.23-0.24 and 0.03-0.05, respectively, indicating significant genetic influence on the DNAm-obesity associations. To further investigate the role of genetic influences, we then categorized the CpGs into different groups: high phenotypic correlation (Rph ≥ 0.2); high phenotypic and genetic correlations (Rph > 0.1 and Ra > 0.5); high phenotypic and low genetic correlations (Rph > 0.1 and Ra < 0.5). Association studies were conducted in the full population and in the monozygotic (MZ) twin-paired design, where genetic influences were controlled. For CpGs with Rph ≥ 0.2, 9, 8, and 22 were associated with BMI, WC, and WHR in the full population, but only 6, 1, and 1 CpGs remained significant after controlling for genetic effects in MZ twin-pair analyses. For CpGs with Rph > 0.1 and Ra > 0.5, genetic factors predominantly drove the association, and none of the 155/155/189 CpGs associated with BMI/WC/WHR in the full population were significant in MZ-paired analyses. For CpGs with Rph > 0.1 and Ra < 0.1, genetic effects were minimal or confounding, with 89, 4, and 17 significant in both full population and MZ-paired analyses.

Conclusions: Our results highlight the significant genetic influences on the DNAm-obesity relationships, which may explain the low replicability of obesity-related DNAm markers. This indicates that genetic influences should be carefully considered in DNAm-related studies.

Background: Telomere homeostasis is pivotal in various biological processes including ontogeny, reproduction, physiological aging, and the onset of numerous diseases such as tumors. In human stem cells and approximately 85% of tumor cells, telomerase formed by TERT and TERC RNA complex is responsible for elongating telomeres. However, the intricate and precise regulatory mechanisms governing telomerase remain largely elusive.

Methods and results: We developed a genome-wide trimolecular fluorescence complementation (TriFC) screen to identify TERC RNA-interacting proteins and found ZC3H15 (Zinc finger CCCH domain-containing protein 15) to interact with telomerase. ZC3H15 interacts with TERT via its N-terminal domain in an RNA-dependent manner. The proximity labeling technique PhastID revealed that ZC3H15 associates with proteins involved in regulation of ribonucleoprotein (RNP) complex biogenesis, snRNP assembly and RNA localization. Deletion of ZC3H15 upregulated telomerase activity but interestingly resulted in shortened telomeres and induced senescence in HTC75 cells, suggesting an unknown mechanism in regulating telomere length. Notably, we found ZC3H15 to associate with GEMs nuclear bodies, and its deletion led to the spatiotemporal fusion of GEMs and Cajal bodies, resulting in the sequestration of telomerase within Cajal bodies and a reduction in telomerase recruitment to telomeres during the S phase. Consistent with these findings, ZC3H15 ablation accumulated TERC precursor RNA.

Conclusions: These observations provide valuable insights into the molecular mechanisms by which ZC3H15 regulates telomerase dynamics and cellular senescence. ZC3H15 may represent a new target for cancer treatment and anti-aging therapies.

Background: Transgender women (transfemales) often undergo gender-affirming hormone therapy (GAHT). However, the testicular impacts of feminising hormones present heterogeneity due to the complexity of testicular regulatory mechanisms.

Method: In this study, we analyzed approximately 49,385 single-cell transcriptomes from transfemale human testicular tissue, comparing cellular composition with that of cisgender male individuals across a range of ages. Our approach included clustering of cell types, identification of marker genes, pseudotime analysis of germ cells, and comprehensive cell-cell interaction analyses. We employed immunohistochemistry, quantitative real-time PCR, and immunostaining to validate the key molecular signatures identified in the pathways of interest.

Results: GAHT led to a significant reduction in spermatogenic cells, accompanied by an unexpected increase in Sertoli cell numbers per seminiferous tubule, suggesting disrupted germ cell-Sertoli cell interactions. Molecular analyses revealed upregulation of genes such as Decorin (DCN), Myoglobin (MB), and Beta-2-Microglobulin (B2M) in Sertoli cells, with enrichment in pathways related to cell adhesion, cytokine response, and wnt signaling. Notably, β-catenin was significantly elevated and translocated into the nucleus of Sertoli cells determined by immunostaining analysis. Additionally, collagen fiber infiltration disrupted the testicular microenvironment, further impairing germline-Sertoli cell communication.

Conclusion: This study provides novel insights into the testicular alterations associated with GAHT in transfemales, particularly highlighting the role of germline-Sertoli cell interactions in testicular injury. Our findings contribute to a deeper understanding of the testicular response to feminizing hormones, offering a foundation for future therapeutic strategies.

Background: Atherosclerosis (AS) is a chronic cardiovascular disease characterized by lipid accumulation and inflammation within arterial walls, leading to plaque formation and cardiovascular events. Circular RNAs (circRNAs) have emerged as key regulators in various diseases, but their role in AS remains poorly understood. This study investigates the protective role and underlying mechanism of circ_HUWE1 in lipid metabolism, macrophage infiltration, inflammation, and gut microbiota modulation in AS.

Methods: Circ_HUWE1 expression was evaluated in coronary artery disease (CAD) patients and in fecal samples from AS patients. An ApoE^-/- mouse model of high-fat diet (HFD)-induced atherosclerosis was employed to assess functional role of circ_HUWE1. Circ_HUWE1 overexpression was induced via adeno-associated virus delivery, and the impact on lipid accumulation, macrophage infiltration, inflammation, and gut microbiota composition was analyzed. Vascular smooth muscle cells (VSMCs) were used for in vitro studies of circ_HUWE1 mechanism of action, including interactions with miR-143-3p and IGFBP5.

Results: Circ_HUWE1 expression was significantly downregulated in CAD patients, fecal samples of AS patients and in HFD-fed ApoE^-/- mice. Circ_HUWE1 overexpression reduced lipid accumulation, plaque formation, and macrophage infiltration in ApoE^-/- mice. Circ_HUWE1 also mitigated dyslipidemia by lowering serum levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein (LDL) while increasing high-density lipoprotein (HDL) levels. Histological analyses showed attenuation of hepatocyte steatosis and adipose tissue enlargement in HFD-fed ApoE^-/- mice. Additionally, circ_HUWE1 reduced proinflammatory cytokines and adhesion molecules, highlighting its anti-inflammatory properties. Furthermore, circ_HUWE1 also modulated the gut microbiota by restoring the abundance of beneficial gut bacteria, Faecalibacterium prausnitzii and Coprococcus comes, which correlated with reduced plaque burden. Mechanistically, circ_HUWE1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-143-3p, thereby upregulating IGFBP5 expression. In vitro, circ_HUWE1 suppressed lipid accumulation and inflammation in VSMCs, effects that were reversed by miR-143-3p overexpression and IGFBP5 knockdown.

Conclusion: Our study demonstrates for the first time that circ-HUWE1 exerts a protective effect against atherosclerosis by regulating lipid metabolism, macrophage infiltration and inflammatory responses through the miR-143-3p/IGFBP5 axis and reshaping the gut microbiota. These findings suggest circ_HUWE1 as a potential therapeutic target for atherosclerosis treatment.

Background: Bone-derived mesenchymal stem cells (BMSCs) are multipotent stem cells capable of differentiating into adipocytes and osteoblasts. Dysfunctional differentiation, characterized by a shift from osteoblastogenesis to adipogenesis, is closely associated with metabolic and senile osteoporosis. The Aldo-keto reductase family 1 member A1 (Akr1A1) enzyme, which utilizes NADPH to reduce aldehyde groups to alcohols, has emerged as a potential regulator. This study investigates the role of reactive oxygen species (ROS) in modulating Akr1A1 expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes.

Results: Our findings demonstrate that increased ROS levels enhance the expression of C/EBP homology protein (CHOP) and Akr1A1 during adipogenic differentiation. Conversely, reduced ROS levels suppress CHOP and Akr1A1 expression in osteogenically committed cells. Functional studies involving Akr1A1 silencing and overexpression revealed that Akr1A1 expression levels dictate MSC lineage commitment without altering ROS production or CHOP expression. Knockdown of Akr1A1 suppressed adipogenesis while promoting osteoblastogenesis, accompanied by upregulation of SIRT1, PGC-1α, TAZ, and other osteogenic transcription factors. In contrast, overexpression of Akr1A1 reduced SIRT1, PGC-1α, and TAZ levels, thereby enhancing adipogenesis and inhibiting osteogenesis. These findings position Akr1A1 as a downstream target of the ROS/CHOP signaling pathway. Using an oxidative stress cell model induced by D-galactose in BMSCs, we confirmed that elevated ROS levels upregulate CHOP and Akr1A1 expression, preferentially driving differentiation into adipocytes over osteoblasts.

Conclusions: Our results reveal that intracellular ROS modulate CHOP and Akr1A1 expression, which regulate commitment to adipogenic and osteogenic lineages. This regulation appears to occur through inhibiting SIRT1-dependent pathways, shedding light on potential therapeutic targets for metabolic and age-related osteoporosis.

Background: Primary cicatricial alopecia (PCA) causes irreversible hair loss due to immune-mediated hair follicle destruction. This study investigates follicle-targeted inflammation in lichen planopilaris (LPP), a major PCA subtype, to identify therapeutic targets.

Methods: Scalp samples from LPP, localized scleroderma (LS), and controls were analyzed using single-cell RNA sequencing and spatial transcriptomics. Cellular composition, spatial localization, and intercellular interactions were examined using differential gene expression and ligand-receptor analyses.

Results: CD8⁺ effector memory T cells (Tem) and macrophages infiltrated hair follicles in LPP, disrupting immune privilege and promoting scarring. Heightened interferon-γ (IFN-γ) signaling and STAT1 activation in Tem cells caused epithelial-mesenchymal transition (EMT) in hair follicle stem cells (HFSCs). Additionally, macrophage-secreted oncostatin M (OSM) impaired HFSC integrity. These mechanisms drive LPP's inflammation and fibrosis.

Conclusions: Our findings identify interferon-γ and oncostatin M as key drivers of LPP pathogenesis, offering targets to reduce follicular scarring and preserve hair growth.

Trial registration: Not applicable.

The emergence of complex tissue architectures from homogeneous stem cell condensates persists as a central enigma in developmental biology. While biochemical signaling gradients have long dominated explanations of organ patterning, the mechanistic interplay between tissue-scale forces and thermodynamic constraints in driving symmetry breaking remains unresolved. This review unveils supracellular actin networks as mechanochemical integrators that establish developmental tensegrity structures, wherein Brownian ratchet-driven polymerization generates patterned stress fields to guide condensate stratification. Central to this paradigm is the dynamic remodeling of actin branches, which transduce mechanical loads into adaptive network architectures through force-modulated capping kinetics and angular reorientation. Such plasticity enables fluid-to-solid phase transitions, stabilizing organ primordia through viscoelastic microdomain formation. Crucially, these biophysical processes are functionally coupled with metabolic reprogramming events, where cytoskeletal strain modulates glycolytic flux and nuclear mechanotransduction pathways to inform differentiation decisions, forging a feedback loop between tissue mechanics and cellular fate specification. Building on these insights, we argue that limitations in current organoid self-organization may originate from incomplete reconstitution of actin-mediated mechanical coherence, and modeling of heterogeneous mesenchymal condensation dynamics offers a strategic framework to decode self-organization trajectories, bridging developmental principles with regenerative design. By synthesizing advances from molecular biophysics to tissue mechanics, this work reframes organogenesis not as a hierarchy of molecular commands, but as an emergent continuum where biochemical, mechanical, and thermodynamic constraints coevolve to sculpt living architectures.

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the HTT gene, which results in a long polyglutamine tract in the huntingtin protein (HTT). One of the earliest key molecular mechanisms underlying HD pathogenesis is transcriptional dysregulation, which is already present in the developing brain. In this study, we searched for networks of deregulated RNAs crucial for initial transcriptional changes in HD- and HTT-deficient neuronal cells.

Results: RNA-seq (including small RNAs) was used to analyze a set of isogenic human neural stem cells. The results were validated using additional methods, rescue experiments, and in the medium spiny neuron-like cells. We observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD and HTT-knockout (HTT-KO) cell lines. The overlapping set of genes upregulated in both HD and HTT-KO cells was enriched in genes associated with DNA binding and the regulation of transcription. We observed substantial upregulation of the following transcription factors: TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2 and FOXD1. Moreover, we identified miRNAs that were consistently deregulated in HD and HTT-KO cells, including miR-214, miR-199, and miR-9. These miRNAs may function in the network that regulates TWIST1 and HTT expression via a regulatory feed-forward loop in HD.

Conclusions: On the basis of overlapping changes in the mRNA and miRNA profiles of HD and HTT-KO cell lines, we propose that transcriptional deregulation in HD at early neuronal stages is largely caused by a deficiency of properly functioning HTT rather than a typical gain-of-function mechanism.

N6-methyladenosine (m⁶A), the most abundant mRNA modification, regulates various mRNA metabolism to affect numerous physiological processes, including immune response. Interestingly, many RNA viruses contain internal m⁶A modifications that contribute to viral replication and innate immune escape process, but its mechanisms remain unclear. Porcine rotavirus (PoRV) is a common cause of diarrhea and gastroenteritis in piglets. Here, we first revealed the m⁶A methylation profile on the PoRV genome. PoRV infection significantly reduced methyltransferase METTL3 expression and induced nuclear-cytoplasmic translocation of METTL3. The structural protein VP6 of PoRV can co-localize with METTL3 in the cytoplasm and bind to METTL3 protein, suggesting that PoRV hijacked the host METTL3 to achieve m⁶A methylation. On the contrary, knockdown of Mettl3 or Ythdf2 in IPEC cells inhibited the replication of PoRV. Mechanistically, silencing of Mettl3 or Ythdf2 enhanced the expression of IRF2 and IFI44L via an increase of mRNA stability of Irf2 and Ifi44l. Furthermore, knockdown of Irf2 and Ifi44l promoted viral replication in IPEC cells. In conclusion, PoRV took full advantage of METTL3 to promote replication, in turn, host reduced own m⁶A methylation to enhance IRF2 and IFI44L to restrain virus infection, suggesting a love-hate relationship between virus and host, and providing novel targets for developing antiviral drugs in the pig industry.