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Results for “Paired Box Transcription Factors”

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PubMed2025

PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.

UNLABELLED: PAX3-FOXO1, an oncogenic transcription factor, drives a particularly aggressive subtype of rhabdomyosarcoma (RMS) by enforcing gene expression programs that support malignant cell states. In this study, we show that PAX3-FOXO1+ RMS cells exhibit altered pyrimidine metabolism and increased dependence on enzymes involved in de novo pyrimidine synthesis, including dihydrofolate reductase (DHFR). Consequently, PAX3-FOXO1+ cells display increased sensitivity to inhibition of DHFR by the chemotherapeutic drug methotrexate, and this dependence is rescued by provision of pyrimidine nucleotides. Methotrexate treatment mimics the metabolic and transcriptional impact of PAX3-FOXO1 silencing, reducing expression of genes related to PAX3-FOXO1-driven malignant cell states. Accordingly, methotrexate treatment slows the growth of multiple PAX3-FOXO1+ tumor xenograft models but not their fusion-negative counterparts. Taken together, these data demonstrate that PAX3-FOXO1 induces cell states characterized by altered pyrimidine dependence and nominates methotrexate as an addition to the current therapeutic arsenal for treatment of these malignant pediatric tumors. SIGNIFICANCE: PAX3-FOXO1+ rhabdomyosarcoma cells and tumors exhibit increased sensitivity to DHFR inhibition via methotrexate, identifying a potential therapeutic vulnerability that can be exploited to treat this aggressive pediatric sarcoma.

Humans↗
PubMed2024

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

Animals↗
PubMed2026

Genome-Wide Characterization of the Apple HD-Zip IV Gene Family and Functional Validation of MdHDZIV3 Under PEG-Induced Osmotic Stress.

The homeodomain-leucine zipper IV (HD-Zip IV) transcription factor subfamily plays essential roles in epidermal development, cuticle formation, lipid metabolism, and environmental adaptation in plants. Despite its biological importance, the HD-Zip IV family has not been systematically characterized in apple (Malus domestica). Here, we identified 17 apple HD-Zip IV genes and named them MdHDZIV1-MdHDZIV17 based on their locations on the chromosomes. The 17 genes showed a nonuniform distribution on eight chromosomes, while the occurrence of both tandem and segmental duplications indicated that family expansion involved more than one duplication mechanism. All MdHDZIV proteins contained the conserved HD, LZ, START, and SAD domains but lacked the MEKHLA domain, consistent with typical HD-Zip IV structural features. Phylogenetic analysis classified MdHDZIV proteins into five groups together with HD-Zip IV members from Arabidopsis thaliana and rice, indicating evolutionary conservation of this subfamily. Collinearity and Ka/Ks analyses revealed that duplicated MdHDZIV gene pairs were mainly subjected to purifying selection. Promoter scanning revealed diverse cis-regulatory motifs associated with hormonal signaling, environmental stress, light response, and epidermal regulation, including ABRE, ARE, W-box, MYC, G-box, and L1-box motifs. Integration of transcriptomic profiling with qRT-PCR validation revealed pronounced tissue-dependent differences in the expression of MdHDZIV genes in leaf, fruit skin, and branch bark. Under PEG6000-induced osmotic stress and NaCl-induced salt stress, 10 candidate MdHDZIV genes displayed gene-specific and stress type-specific expression patterns, with MdHDZIV3 showing strong induction under PEG6000 treatment. Functional validation in apple calli showed that MdHDZIV3 overexpression enhanced PEG tolerance, increased fresh weight, elevated SOD and POD activities, and reduced MDA accumulation under osmotic stress. These findings provide a genome-wide framework for understanding the apple HD-Zip IV gene family.

abiotic stress↗
PubMed2025

NrdR in Streptococcus and Listeria spp.: DNA Helix Phase Dependence of the Bacterial Ribonucleotide Reductase Repressor.

NrdR is a universal transcriptional repressor of bacterial genes coding for ribonucleotide reductases (RNRs), essential enzymes that provide DNA building blocks in all living cells. Despite its bacterial prevalence, the NrdR mechanism has been scarcely studied. We report the biochemical, biophysical, and bioinformatical characterization of NrdR and its binding sites from two major bacterial pathogens of the phylum Bacillota Listeria monocytogenes and Streptococcus pneumoniae. NrdR consists of a Zn-ribbon domain followed by an ATP-cone domain. We show that it forms tetramers that bind to DNA when loaded with ATP and dATP, but if loaded with only ATP, NrdR forms various oligomeric complexes unable to bind DNA. The DNA-binding site in L. monocytogenes is a pair of NrdR boxes separated by 15-16 bp, whereas in S. pneumoniae, the NrdR boxes are separated by unusually long spacers of 25-26 bp. This observation triggered a comprehensive binding study of four NrdRs from L. monocytogenes, S. pneumoniae, Escherichia coli, and Streptomyces coelicolor to a series of dsDNA fragments where the NrdR boxes were separated by 12-27 bp. The in vitro results were confirmed in vivo in E. coli and revealed that NrdR binds most efficiently when there is an integer number of DNA turns between the center of the two NrdR boxes. The study facilitates the prediction of NrdR binding sites in bacterial genomes and suggests that the NrdR mechanism is conserved throughout the bacterial domain. It sheds light on RNR regulation in Listeria and Streptococcus, and since NrdR does not occur in eukaryotes, opens a way to the development of novel antibiotics.

Ribonucleotide Reductases↗
PubMed2025

Targeting FOXK2 in triple-negative breast cancer: Role of the P53/MCAS1/miR-211-5p regulatory axis.

Forkhead box K2 (FOXK2) is over-expressed in several human malignancies, yet how it is regulated triple-negative breast cancer (TNBC) remained unclear. We aimed to clarify whether FOXK2 drives TNBC progression, and elucidate the upstream molecular circuitry that controls FOXK2 abundance. FOXK2 mRNA and protein were quantified by qPCR and Western blot in 30 paired TNBC and adjacent tissues. Some assays assessed proliferation, migration and invasion after FOXK2 knockdown or overexpression. Bioinformatics predicted miR-211-5p targeting FOXK2 and lncRNA MCM3AP-AS1 (MCAS1) targeting miR-211-5p. RNA immunoprecipitation (RIP) and dual-luciferase assays validated these interactions. RNA pulldown, mass spectrometry and ChIP identified p53 binding to the MCAS1 promoter. FOXK2 was upregulated in TNBC tissues as opposed to the para-carcinoma tissues. FOXK2 silencing significantly reduced proliferation, migration and invasion, whereas overexpression accelerated these phenotypes. Mechanistically, MCAS1 acts as a sponge for miR-211-5p, ultimately protecting its target gene FOXK2 from degradation. Furthermore, employing RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays, our studies revealed a direct interaction between P53 and the promoter of MCAS1. This interaction resulted in the suppression of MCAS1 transcription. Clinical samples from TNBC patients further confirmed a correlation between FOXK2 expression and tumor size, lymphatic involvement, as well as the expression level of Ki-67. Our findings unveil a novel P53/MCAS1/miR-211-5p/FOXK2 regulatory axis that dictates TNBC aggressiveness. FOXK2 may sever as both a prognostic biomarker and a therapeutic target in TNBC.

Humans↗
PubMed2026

Additional PAX3 Variants for Dominant Blue Eyes in Cats.

Since the recent publication of the first feline variant of the PAX3 (Paired Box 3) gene associated with blue eyes and minimal white spotting (DBE, Dominant Blue Eyes), three further variants of PAX3 have been reported in felines. However, these four variants do not account for all the different feline lines that exhibit DBE. Whole-genome sequencing using short-read and long-read technologies identified a large complex structural variant involving two deletions and an inversion in a purebred line of British shorthair and longhair cats. All 39 British cats with a BDE phenotype were heterozygous for the variant, that was absent in 47 non-DBE cats and 16 DBE cats from other breeding lines. The purebred British shorthair founder female named Nadeya was also heterozygous for the variant, and the segregation of the variant is consistent with dominant inheritance. We named this NC_058375.1:g.[205097674_207411974del;207411975_211290497inv;211290498_211387174del] variant the DBENAD (Nadeya Dominant Blue Eyes) allele. In addition, a candidate gene approach identified a nonsense variant, XM_019838731.3:c.784C>T, in the fifth exon of PAX3 in a second breeding line originating from a female named Marusya. The segregation of this nonsense variant is consistent with dominant inheritance, and a perfect genotype-phenotype correlation was observed in the 16 cats from this line, so we propose that this sixth variant of PAX3 represents the DBEMARU (Marusya Dominant Blue Eyes) allele in the domestic cat. Our study has identified two further variants of the PAX3 gene associated with DBE in domestic cats, which will help to improve genotyping of the breeding stock.

Animals↗