Cellular and Molecular Life Sciences最新文献

Extravillous trophoblasts (EVTs) play essential roles in placental development by anchoring the placenta, invading the maternal decidua, and remodeling spiral arteries. TCF7L2 is known to be expressed in human placental tissues and EVTs, and it controls EVT motility. However, the targets of TCF7L2 in trophoblasts and the mechanism by which it contributes to early trophoblast differentiation are largely unknown. Here, using trophoblast stem cells (TSCs), we investigate the expression patterns of TCF7L2 during trophoblast lineage differentiation, revealing that its expression gradually elevates throughout EVT formation. Loss-of-function studies uncover that TCF7L2 is implicated in the proliferation of TSCs and is essential for EVT formation. Conversely, overexpression of TCF7L2 hinders TSC differentiation into STs. We identify TCF7L2 binding sites across the genome in TSCs and EVTs. Integrative analyses of TCF7L2 targets with global gene expression profiles unveil that TCF7L2 facilitates EVT formation by directly activating extracellular matrix organization while suppressing genes linked to the cell cycle. Moreover, overlap analyses of TCF7L2 targets with those of other EVT factors reveal that TCF7L2 collaborates with other EVT factors to promote EVT formation. In summary, our findings highlight context-specific functions of TCF7L2 in the trophoblast lineage.

Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with tumor immune evasion posing a major challenge to effective immunotherapy. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation, are critical regulators of protein function and stability, profoundly influencing tumor immunogenicity and the tumor immune microenvironment. This review comprehensively examines how PTMs modulate key immune processes in CRC, such as antigen presentation, immune cell infiltration, and immune checkpoint regulation. We discuss PTM-mediated mechanisms that shape T cell exhaustion, macrophage polarization, and immunosuppressive cytokine networks within the tumor microenvironment. Moreover, we highlight the impact of PTMs on therapeutic response and resistance to immune checkpoint blockade and adoptive cell therapies. Emphasis is placed on emerging PTM-targeted strategies to enhance antitumor immunity and overcome immunotherapy resistance. Finally, we explore advances in multi-omics technologies and proteomic profiling that promise to accelerate the identification of PTM biomarkers and novel therapeutic targets. By integrating mechanistic insights with translational perspectives, this review aims to provide a foundation for leveraging PTMs to optimize immunotherapeutic approaches in colorectal cancer.

During a lifetime, normal cells accumulate thousands of changes in their genome sequence. These changes, termed somatic mutations, have mostly been studied in the context of cancer, but their presence in normal tissues is ubiquitous and widespread. Somatic mutation accompanies the aging process and is influenced by genetic and environmental factors. Differently from gene expression or imaging data, which fluctuate over time, somatic variants are non-reversible marks in the genome and accumulate over time. This property can be exploited to track the history of a cell, from conception to old age, providing information that cannot be acquired via classical histological tissue inspection nor other types of omics data. Mutations can track embryonic development, measure how clones compete in a tissue over time, or report the mutational processes active in cells and tissues throughout life. We discuss selected examples and emphasize how somatic mutation analysis can enable expanding applications at the service of physiology and cell biology, as well as a deeper understanding of the aging process.

Calcium (Ca²⁺) is an essential regulator of cardiac function. Particularly, Ca²⁺ is the primary link between the electrical signals regulating contractility of the myocytes and thus allowing the heart chambers to relax and refill completely with blood. Additionally, Ca²⁺ controls numerous other activities including gene transcription, cell growth, and survival. The abnormal Ca²⁺ regulation and cycling in the cardiomyocyte following various stressor's, insults and during cardiac disease development has been found to be a primary culprit leading to cellular dysfunction and potentially to cell death and ultimately resulting in impaired cardiac function and disease development. This review aims to briefly describe our current understanding regarding the role of Ca²⁺ signaling in cardiac function under physiological and stressed conditions.

Sepsis-associated acute kidney injury (SAKI) is a severe condition associated with high mortality and long-term complications. Currently, there is no effective strategy to halt AKI chronicization. Stress-induced senescence of renal tubular epithelial cells (RTECs) is a pivotal driving mechanism in the AKI-CKD transition. Previous scRNA-seq revealed that the expression of immediate early response gene 3 (IER3) was markedly upregulated in the senescent RTECs of patients with AKI and that the IER3⁺RTEC subpopulation exhibited diminished differentiation potential and impaired self-renewal capacity. However, the role of IER3 in RTEC stress-induced senescence following AKI remains unclear. In this study, we found that knockout of IER3 reduced mortality rates, alleviated renal injury, mitigated renal maladaptive fibrotic repair, and concurrently inhibited RTEC stress-induced senescence after SAKI. Further RNA-seq of IER3^-/- mouse renal tissues revealed significant upregulation of peroxiredoxin 5 (PRDX5) in the absence of IER3. Inhibition of PRDX5 blocked the effects of IER3 knockout on RTEC stress-induced senescence under septic conditions. Intriguingly, we found that IER3 interacted with the presenilin-associated rhomboid-like gene (Parl) and reduced its shear activity. This interaction also inhibited the cleavage and subsequent mitochondrial translocation of cytoplasmic PRDX5, leading to decreased mitochondrial levels in PRDX5 and impaired antioxidant capacity. These changes resulted in oxidative mitochondrial damage and abnormal perinuclear clustering of mitochondria, which promote stress-induced cellular senescence and ultimately facilitates the transition from AKI to CKD. In conclusion, our findings suggest that IER3 might induce RTEC senescence and exacerbate the AKI-CKD transition in sepsis-associated AKI by inhibiting mitochondrial translocation of PRDX5.

Background: Glioma is the most frequently diagnosed brain tumor in adults worldwide which is associated with unfavorable prognosis and survival time. However, the understanding of glioma progression remains limited.

Methods: The cell proliferation in glioma cells were monitored by EdU incorporation and CCK-8 assays. Glioma cell invasion and migration were assessed by Transwell assay. In vivo tumorigenesis were detected by xenograft study with bioluminescence imaging. qRT-PCR, RNA FISH, IHC or western blot were used to detect circEPHB4, MRPS16, YBX1, RBBP6 and other molecules expression. The associations between YBX1 and MRPS16 mRNA, as well as between circEPHB4 and YBX1, were detected by RNA immunoprecipitation (RIP) and RNA pull-down assays. In addition, the ubiquitination of YBX1 and RBBP6-YBX1 interaction were assessed by co-immunoprecipitation (co-IP).

Results: Knockdown of circEPHB4 or MRPS16 inhibited glioma progression in vitro and in vivo. circEPHB4 promoted glioma cell proliferation, migration, and invasion via increasing MRPS16 expression in vitro. At the post-transcriptional level, circEPHB4 enhanced MRPS16 mRNA stability through YBX1-mediated m⁵C modification in vitro. At the post-translational level, RBBP6 catalyzed the ubiquitination of YBX1, and circEPHB4 competed with RBBP6 to bind YBX1 to inhibit the ubiquitin-proteasomal degradation of YBX1 in vitro. circEPHB4 interacted with YBX1 to promote glioma cell growth via inducing MRPS16 in vitro and in vivo.

Conclusion: circEPHB4 bound to YBX1 to inhibit RBBP6-mediated degradation and increase its expression, thus enhancing MRPS16 mRNA stability via m⁵C modification, and ultimately promoting glioma progression.

Most prostate cancer risk variants reside in noncoding DNA, but connecting germline alleles to lineage transcription factor (TF) programs has been challenging. We developed immunoprecipitation-coupled SNPs-seq (IP-SNPs-seq), enabling high-throughput, allele-specific, TF-resolved interrogation of candidate regulatory variants. Screening 903 prostate cancer-associated SNPs with androgen receptor (AR) immunoprecipitation, we identified multiple alleles with biased AR binding and convergent evidence from eQTL and ChIP-seq datasets. Among these, rs7600820 emerged as a functional enhancer variant: the risk G allele conferred stronger reporter activity, heightened AR responsiveness to dihydrotestosterone, and increased ODC1 expression; chromatin profiling and Hi-C revealed an active enhancer loop to the ODC1 promoter. ODC1 was consistently upregulated in primary and metastatic tumors across independent cohorts, associated with adverse clinicopathologic features, and required for prostate cancer cell proliferation. Gene-set enrichment analyses linked high ODC1 expression to MYC target signatures, positioning ODC1 as a clinically relevant, AR-regulated oncogenic node that integrates germline risk with core prostate cancer circuitry. IP-SNPs-seq thus provides a scalable route from association to mechanism, broadly applicable to diverse TFs and diseases, and nominates the AR-rs7600820-ODC1 axis as a potential biomarker and therapeutic vulnerability in androgen-driven prostate cancer.

NADPH oxidase 3 (Nox3), expressed in the endolymphatic duct and sac within the vestibule of the inner ear, is essential for otoconia formation. Mice with functionally deficient Nox3 exhibit a "head-tilt" phenotype. Recently, we reported that Nox3 expression in the cochlea is induced by aging, cisplatin treatment, and intense noise exposure, contributing to the primary source of reactive oxygen species (ROS) and causing acquired sensorineural hearing loss. However, its expression and function outside the inner ear remain poorly characterized. To explore novel Nox3 functions, we used Nox3-Cre;tdTomato mice, in which Cre recombinase (Cre) is knocked into the ATG site of Nox3, enabling visualization of Nox3 expression via tdTomato fluorescence. We identified Nox3 expression in retinal ganglion cells (RGCs) and GABAergic amacrine cells (ACs). The tdTomato-positive cells increased by 2 months of age and then plateaued in Nox3-Cre^+/-;tdTomato^+/+ (heterozygous knock-in [KI], hereafter HT Nox3-knockout [KO]) mice, while in Nox3-Cre^+/+;tdTomato^+/+ (homozygous KI, hereafter Nox3-KO) mice, the increase occurred by 12 months, suggesting that Nox3-derived ROS are toxic to RGCs and ACs. Additionally, Nox3-KO mice showed reduced a-, b-, and scotopic threshold response (STR)-waves in electroretinogram (ERG) compared to WT mice. Treatment with cisplatin, a well-known toxic agent for the retina and optic nerve, reduced tdTomato-positive cells in the retinae of 2-month-old HT Nox3-KO mice but not in Nox3-KO mice, compared to age-matched controls. Nox3-KO retinae developed normally. Thus, Nox3 is expressed in RGCs and ACs to regulate retinal function; however, excessive Nox3-derived ROS cause toxicity under pathological conditions, including aging.

The cerebellum is a highly organized brain structure best known for its roles in motor control and sensorimotor integration. While cerebellar development has traditionally been attributed to intrinsic genetic programs and local cell-cell interactions, emerging evidence indicates that extrinsic cues particularly signals from the meninges also play a critical role in shaping its maturation. Studies indicate that the meninges release cytokines, chemokines, and growth factors including CXCL12, IGF-1, IL-33, FGF2, TGF-β, and retinoic acid that influence granule cell precursor (GCPs) proliferation, Purkinje cell (PC) maturation, radial glia organization, and synaptic refinement. In addition, meningeal immune cells form a dynamic interface that potentially shapes neuronal positioning and cerebellar circuit formation. Disruption of these signals through genetic mutations, immune dysregulation, or environmental insults lead to impaired foliation, ectopic neuronal migration, and aberrant cerebellar architecture. This review focuses on in vivo findings supporting an emerging concept of the meningeal-cerebellar axis in development. Understanding cerebellar maturation within this broader context offers new perspectives on the origins of neurodevelopmental disorders and points toward novel avenues for therapeutic intervention.