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1. Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS/YARS1 Depletion

   Jhanji, Megha; Bhan, Ashita; Arrowood, Colin; Yakout, Dina W; Shroff, Ankit; McManus, Danielle; Gifford, Henrietta; Vacharasin, Janay; Lizarraga, Sofia B; Nazarko, Taras Y; et al (June 2025, Wiley)

   Serum tyrosine and phenylalanine levels increase during aging and age-associated disorders. We previously showed that tyrosyl-tRNA synthetase (TyrRS/YARS1) is reduced in Alzheimer's Disease (AD) brains, and tyrosine and phenylalanine decrease TyrRS in neurons. Here, we found that tau is a negative regulator, whereas estrogen and leucine act as positive regulators of TyrRS. Young female mice exhibit increased TyrRS in the cortex compared to male mice. Notably, young Tau knockout male, but not female mice showed increased cortical TyrRS. Tau accumulation in middle-aged female mice did not decrease cortical TyrRS compared to males, suggesting that middle aged females are resilient to tau-mediated TyrRS depletion. Tyrosine and phenylalanine treatment decreased tubulin tyrosination, activated DNA repair pathways, and protected against etoposide (ETO) and camptothecin (CPT)-induced toxicity, respectively, in neurons. While tyrosine facilitated topoisomerase 1 (TOP1) recruitment to chromatin and inhibited global transcription, in contrast, phenylalanine recruited topoisomerase 2 beta (TOP2β) to chromatin and stimulated global transcription. Furthermore, tyrosine decreased the presence of DNA fragments in a comet assay whereas phenylalanine increased them. Addition of cis-resveratrol (cis-RSV) protected against tyrosine-induced transcription inhibition by facilitating the recruitment of both TOP1 and TOP2β to chromatin and increasing tubulin tyrosination. Moreover, cis-RSV decreased both total and phosphorylated tau and protected neurons against amyloid beta (Aβ)-induced neurite degeneration and DNA damage. Gene expression profiling using human embryonic stem cell (hESC)-derived neurons demonstrated that cis-RSV is a broad-spectrum neuroprotective and anti-viral agent. In contrast, trans-RSV mimics phenylalanine-induced gene expression, including downregulation of long genes and induction of an AD-like gene expression signature. This work suggests that age and disease-associated increases in serum tyrosine and phenylalanine levels would activate neuronal DNA repair while inhibiting transcription and tubulin tyrosination. cis-RSV protects against their toxicity by restoring tubulin tyrosination, TOP1 and TOP2β-mediated transcription, and decreasing tau in primary neurons. 

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2. Transcription factor-promoter interactions for PSY / PSYR -mediated regulation of root growth

   https://doi.org/10.1101/2025.09.29.679155  

   Liao, Jin C-Y; Bågman, Anne-Maarit; Liu, Angie J; Shim, Yejin; Brady, Siobhán M; Ronald, Pamela C (September 2025, bioRxiv)

   Abstract Precisecis-regulatory control of gene expression is essential for plant growth. InArabidopsis thaliana, PLANT PEPTIDE CONTAINING SULFATED TYROSINE (PSY) peptides and their receptors (PSYRs) mediate growth-stress trade-offs, yet the transcriptional regulation of these genes remains poorly understood. Here, we mapped transcription factor (TF)-promoter interactions for ninePSYand threePSYRgenes by combining high-throughput enhanced yeast one-hybrid screening with DNA Affinity Purification sequencing (DAP-seq) data, uncovering 1,207 interactions that reveal both shared and gene-specific regulatory relationships, defining the global TF-promoter interaction network of thePSY/PSYRpathway. Functional analysis of 25 TF mutants identified 12 regulators that significantly influence root growth, most acting as repressors. Of these, CYTOKININ RESPONSE FACTOR 10 (CRF10) emerged as a strong growth inhibitor. We identified a CRF10-binding motif in thePSYR3promoter using DAP-seq data and validated it using eY1H. This motif is also located in the last 3′ terminal exon ofTopoisomerase 3A(TOP3A). Guided by these insights, we used CRISPR/Cas9-mediated promoter editing to delete a small region encompassing or flanking a functional TF-binding site (TFBS). Removal of this motif, or of its surrounding region, enhanced root growth, yielding variants that retained root length comparable to thecrf10mutant. Our results suggest that the observed root growth phenotype results either from disruption of the CRF10 binding motif or from the mutation in theTOP3Aexon. 

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3. Manganese‐dependent transcription regulation by MntR and PerR in Thermus thermophilus HB8

   https://doi.org/10.1111/mmi.15278  

   Barrows, John K; Stubbs, Kamya A; Padilla‐Montoya, Irina F; Leeper, Thomas C; Van Dyke, Michael W (May 2024, Molecular Microbiology)

   Abstract Bacteria contain conserved mechanisms to control the intracellular levels of metal ions. Metalloregulatory transcription factors bind metal cations and play a central role in regulating gene expression of metal transporters. Often, these transcription factors regulate transcription by binding to a specific DNA sequence in the promoter region of target genes. Understanding the preferred DNA‐binding sequence for transcriptional regulators can help uncover novel gene targets and provide insight into the biological role of the transcription factor in the host organism. Here, we identify consensus DNA‐binding sequences and subsequent transcription regulatory networks for two metalloregulators from the ferric uptake regulator (FUR) and diphtheria toxin repressor (DtxR) superfamilies inThermus thermophilusHB8. By homology search, we classify the DtxR homolog as a manganese‐specific, MntR (TtMntR), and the FUR homolog as a peroxide‐sensing, PerR (TtPerR). Both transcription factors repress separate ZIP transporter genes in vivo, andTtPerR acts as a bifunctional transcription regulator by activating the expression of ferric and hemin transport systems. We showTtPerR andTtMntR bind DNA in the presence of manganese in vitro and in vivo; however,TtPerR is unable to bind DNA in the presence of iron, likely due to iron‐mediated histidine oxidation. Unlike canonical PerR homologs,TtPerR does not appear to contribute to peroxide detoxification. Instead, theTtPerR regulon and DNA binding sequence are more reminiscent of Fur or Mur homologs. Collectively, these results highlight the similarities and differences between two metalloregulatory superfamilies and underscore the interplay of manganese and iron in transcription factor regulation. 

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4. DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation

   https://doi.org/10.1038/s44319-025-00526-1  

   Leismann, Jessica; Kanta, Styliani-Eirini; Amar, Ishita; Szczepińska, Anna; Mielnicka, Monika; Petrosino, Giuseppe; Busch, Anke; Scheibe, Marion; Wang, Pengxiang; Wang, Yuan; et al (September 2025, EMBO Reports)

   Abstract Silencing evolutionary young retrotransposons by cytosine DNA methylation is essential for spermatogenesis, as failure to methylate their promoters leads to reactivation, meiotic failure, and infertility. How retrotransposons reactivate in the absence of DNA methylation is poorly understood. We show that upon defective DNA methylation, distinct retrotransposon families display unique expression patterns and chromatin landscapes during mouse spermatogenesis. We find that their reactivation in meiotic spermatocytes correlates with the loss of bivalent H3K4me3-H3K27me3 chromatin marks. Through proteomics and chromatin profiling, we identify NRF1 as a DNA methylation-sensitive transcription factor that transactivates unmethylated retrotransposons. Conditional germline knockout ofNrf1in the absence of DNA methylation rescues the silencing of the most mutagenic retrotransposon in mice, namely Intracisternal A-particle or IAP. Our findings reveal that chromatin modifications together with a DNA methylation-sensitive transcription factor regulate retrotransposon expression in the absence of DNA methylation in spermatogenesis, revealing a mechanism by which retrotransposons proliferate in the germline after evading DNA methylation-based silencing. 

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5. Maternal upbringing and selective breeding for voluntary exercise behavior modify patterns of DNA methylation and expression of genes in the mouse brain

   https://doi.org/10.1111/gbb.12858  

   Latchney, Sarah E; Cadney, Marcell D; Hopkins, Anthony; Garland, Theodore (December 2023, Genes, Brain and Behavior)

   Abstract Selective breeding has been utilized to study the genetic basis of exercise behavior, but research suggests that epigenetic mechanisms, such as DNA methylation, also contribute to this behavior. In a previous study, we demonstrated that the brains of mice from a genetically selected high runner (HR) line have sex‐specific changes in DNA methylation patterns in genes known to be genomically imprinted compared to those from a non‐selected control (C) line. Through cross‐fostering, we also found that maternal upbringing can modify the DNA methylation patterns of additional genes. Here, we identify an additional set of genes in which DNA methylation patterns and gene expression may be altered by selection for increased wheel‐running activity and maternal upbringing. We performed bisulfite sequencing and gene expression assays of 14 genes in the brain and found alterations in DNA methylation and gene expression forBdnf,Pde4dandGrin2b. Decreases inBdnfmethylation correlated with significant increases inBdnfgene expression in the hippocampus of HR compared to C mice. Cross‐fostering also influenced the DNA methylation patterns forPde4din the cortex andGrin2bin the hippocampus, with associated changes in gene expression. We also found that the DNA methylation patterns forAtrxandOxtrin the cortex andAtrxandBdnfin the hippocampus were further modified by sex. Together with our previous study, these results suggest that DNA methylation and the resulting change in gene expression may interact with early‐life influences to shape adult exercise behavior. 

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