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Summary: Aberrant alternative splicing (AS) contributes to leukemogenesis, but reports on the clinical and biological implications of aberrant AS in acute myeloid leukaemia (AML) remain limited. Here, we used RNA‐seq to analyse AS in AML cells from 341 patients, comparing them to healthy CD34+ haematopoietic stem cells (HSCs). Our findings highlight distinct AS patterns in the nuclear transcription factor Y subunit alpha (NFYA) gene, with two main isoforms: NFYA‐L (Long) and NFYA‐S (Short), differing in exon 3 inclusion. Patients with lower NFYA‐L but higher NFYA‐S expression, termed NFYA‐S predominance, displayed more favourable characteristics and better outcomes following intensive chemotherapy, regardless of age and European LeukemiaNet risk classification, compared to those with higher NFYA‐L but lower NFYA‐S expression, termed NFYA‐L predominance. The prognostic effects were validated using The Cancer Genome Atlas cohort. Transcriptome analysis revealed upregulated cell cycle genes in NFYA‐S predominant cases, resembling those of active HSCs, demonstrating relative chemosensitivity. Conversely, NFYA‐L predominant cases, as observed in KMT2A‐rearranged leukaemia, were associated with relative chemoresistance. NFYA‐S overexpression in OCI‐AML3 cells promoted cell proliferation, S‐phase entry and increased cytarabine sensitivity, suggesting its clinical and therapeutic relevance in AML. Our study underscores NFYA AS as a potential prognostic biomarker in AML. [ABSTRACT FROM AUTHOR]

This research investigates the intricate involvement of nuclear Transcription Factor Y Subunit Alpha (NFYA) in the advancement of castration-resistant prostate cancer (CRPC) and its consequential impact on early Growth Response 4 (EGR4) expression. NFYA demonstrates a significant elevation in CRPC tissues and cell lines, displaying robust upregulation in metastatic prostate cancer (mPCa) samples, closely associated with the Gleason score. Immunohistochemistry validates heightened nuclear staining of NFYA in CRPC patients, highlighting its crucial role in the progression of advanced prostate cancer. Silencing NFYA through siRNA in androgen-independent cell lines markedly impedes cell growth and migration, emphasizing NFYA's pivotal role in promoting CRPC behavior. RNA-seq analysis identifies EGR4 as a downstream target of NFYA, with both genes consistently upregulated in CRPC. Validating this finding, heightened expression of EGR4 is observed in CRPC samples. In vivo studies utilizing a mouse model demonstrate that NFYA silencing substantially inhibits LNCaP-AI/22RV1shNFYA xenograft tumor growth, accompanied by reduced expression of EGR4 and Ki67. This comprehensive study reveals the multifaceted role of NFYA in CRPC progression, elucidates its downstream impact on EGR4, and underscores the therapeutic potential of targeting NFYA to inhibit CRPC growth in vivo. These findings contribute valuable insights into potential therapeutic strategies for managing CRPC. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the role of Jumonji AT Rich Interacting Domain 2 (JARID2) in regulating triple-negative breast cancer (TNBC) stemness and its mechanism. Research design and methods: Bioinformatics analysis examined JARID2 expression, prognosis, and transcription factors. Quantitative polymerase chain reaction, western blot, and immunohistochemistry detected expression. Dual luciferase reporter gene and chromatin immunoprecipitation assays verified binding. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay detected viability and proliferation. Sphere formation assay detected the sphere formation efficiency. Flow cytometry detected CD44+/CD24− -marked stem cells. A xenograft tumor model verified the effect of JARID2 in vivo. Results: JARID2 and nuclear transcription factor Y subunit α (NFYA) were upregulated in TNBC tissues and positively correlated. Knockdown of JARID2 or NFYA inhibited cell stemness by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. Enforced JARID2 expression rescued the suppressive effect of NFYA knockdown on the PI3K/AKT signaling pathway and cell stemness. Knockdown of JARID2 inhibited tumor growth and cell stemness in mice but was alleviated by concurrent overexpression of NFYA. Conclusions: NFYA promotes TNBC cell stemness by upregulating JARID2 expression and regulating the PI3K/AKT signaling pathway, suggesting JARID2 as a potential target for innovating drugs that target TNBC stem cells. [ABSTRACT FROM AUTHOR]

Objective: To analyze the expression and clinical significance of nuclear transcription factor Y subunit A (NFYA) in hepatocellular carcinoma (HCC) based on public databases and studies in vitro cell lines and tumor tissues. Methods: Transcriptome and clinical data of HCC patients were obtained and analyzed from the TCGA database. The expression of NFYA in HCC cell lines and patient tissues was validated through qRT-PCR and immunohistochemical staining. The correlation between NFYA expression levels and clinical-pathological features, prognosis, potential pathogenic mechanisms and immune cell infiltration was analyzed using univariate and multifactorial Cox regression analysis, Kaplan-Meier analysis, GO and KEGG analysis. Results: NFYA mRNA expression was significantly increased in HCC tissues compared to normal liver tissues, and this phenomenon was also confirmed in HCC cell lines. In the study cohort of HCC tissues, NFYA protein expression was significantly upregulated. NFYA mRNA expression level was correlated with tumor histological grade, T stage, and pathological stage. HCC patients with high NFYA expression had a worse prognosis. NFYA-related genes in HCC were mainly enriched in biological processes such as nuclear cleavage and cell cycle. The analysis of the tumor microenvironment suggested that high NFYA expression was associated with lower immune cell infiltration and stromal cell infiltration, and that NFYA expression was positively correlated with the expression of multiple immune checkpoint genes. Conclusion: NFYA is overexpressed and associated with poor prognosis in HCC patients and may serve as a potential prognostic marker. This activity of NFYA in HCC might be related to its influence on cell cycle and immune cell infiltration. [ABSTRACT FROM AUTHOR]

Embryonic genome activation (EGA) is a critical step during embryonic development. Several transcription factors have been identified that play major roles in initiating EGA; however, this gradual and complex mechanism still needs to be explored. In this study, we investigated the role of nuclear transcription factor Y subunit A (NFYA) in bovine EGA and bovine embryonic development and its relationship with the platelet-derived growth factor receptor-β (PDGFRβ) by using a potent selective activator (PDGF-BB) and inhibitor (CP-673451) of PDGF receptors. Activation and inhibition of PDGFRβ using PDGF-BB and CP-673451 revealed that NFYA expression is significantly (p < 0.05) affected by the PDGFRβ. In addition, PDGFRβ mRNA expression was significantly increased (p < 0.05) in the activator group and significantly decreased (p < 0.05) in the inhibitor group when compared with PDGFRα. Downregulation of NFYA following PDGFRβ inhibition was associated with the expression of critical EGA-related genes, bovine embryo development rate, and implantation potential. Moreover, ROS and mitochondrial apoptosis levels and expression of pluripotency-related markers necessary for inner cell mass development were also significantly (p < 0.05) affected by the downregulation of NFYA while interrupting trophoblast cell (CDX2) differentiation. In conclusion, the PDGFRβ-NFYA axis is critical for bovine embryonic genome activation and embryonic development. [ABSTRACT FROM AUTHOR]

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The Polyribonucleotide nucleotidyltransferase 1 gene (PNPT1) encodes polynucleotide phosphorylase (PNPase), a 3′-5′ exoribonuclease involved in mitochondrial RNA degradation and surveillance and RNA import into the mitochondrion. Here, we have characterized the PNPT1 promoter by in silico analysis, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), chromatin immunoprecipitation (ChIP), siRNA-based mRNA silencing and RT-qPCR. We show that the Specificity protein 1 (SP1) transcription factor and Nuclear transcription factor Y (NFY) bind the PNPT1 promoter, and have a relevant role regulating the promoter activity, PNPT1 expression, and mitochondrial activity. We also found in Kaplan–Meier survival curves that a high expression of either PNPase, SP1 or NFY subunit A (NFYA) is associated with a poor prognosis in liver cancer. In summary, our results show the relevance of SP1 and NFY in PNPT1 expression, and point to SP1/NFY and PNPase as possible targets in anti-cancer therapy. [ABSTRACT FROM AUTHOR]

Summary: Legume crops contribute a great portion of clean nitrogen (N) to agro‐ecosystems through symbiotic N2 fixation in the nodule; however, the nodulation is always inhibited by high N availability which is known as the N inhibitory effect through largely unknown mechanisms.We functionally investigated miR169c‐GmNFYA‐C‐GmENOD40 under multiple N conditions in soybean (Glycine max) (ENOD, Early Nodulin; NFYA, Nuclear Factor‐Y Subunit A). We elucidated their regulatory roles in soybean nodulation through analyzing expression patterns, micro–messenger RNA (miRNA–mRNA) interactions, phenotypes of transgenic soybean plants and genetic interactions.We found that miR169c expression was induced by high N, whereas its target GmNFYA‐C was preferentially expressed in nodules and induced by rhizobium inoculation. Overexpression of miR169c inhibited nodulation through targeting 3′‐UTR of GmNFYA‐C, whereas knockout miR169c through CRISPR‐cas9 promoted nodulation. However, overexpression of GmNFYA‐C promoted soybean nodulation through facilitating rhizobium infection and increasing the expression of symbiotic signaling gene GmENOD40. Besides, GmNFYA‐C directly induced the expression of GmENOD40. In addition, overexpression of GmNFYA‐C without the target site of miR169c partially attenuated the inhibitory effect of high N on soybean nodulation.We discovered a new regulatory pathway involving the miR169c‐NFYA‐C‐ENOD40 module that regulates soybean nodulation in response to N availability. This pathway provides substantial new insights into the mechanisms underlying the N inhibitory effect on nodulation. [ABSTRACT FROM AUTHOR]

Recent studies have revealed that microRNAs (miRNAs) regulate plant adaptive responses to nutrient deprivation. However, the functional significance of miRNAs in adaptive responses to nitrogen (N) limitation remains to be explored. The Arabidopsis miR169 was strongly down-regulated, whereas its targets, NFYA (Nuclear Factor Y, subunit A) family members, were strongly induced by nitrogen N starvation. Analysis of the expression of miR169 precursors showed that MIR169a was substantially down-regulated in both roots and shoots by N starvation. Accumulation of the NFYA family members was suppressed in transgenic Arabidopsis with constitutive expression of MIR169a. Transgenic Arabidopsis plants overexpressing MIR169a accumulated less N and were more sensitive to N stress than the wild type. N sensitivity of 35S::MIR169a might be attributable to impaired uptake systems. These results provide evidence that miRNAs have functional roles in helping plants to cope with fluctuations in N availability in the soil. [ABSTRACT FROM AUTHOR]