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Abstract Plants respond to wounding stress by changing gene expression patterns and inducing the production of hormones including jasmonic acid. This wounding transcriptional response activates specialized metabolism pathways such as the glucosinolate pathways in Arabidopsis thaliana. While the regulatory factors and sequences controlling a subset of wound-response genes are known, it remains unclear how wound response is regulated globally. Here, we how these responses are regulated by incorporating putative cis-regulatory elements, known transcription factor binding sites, in vitro DNA affinity purification sequencing, and DNase I hypersensitive sites to predict genes with different wound-response patterns using machine learning. We observed that regulatory sites and regions of open chromatin differed between genes upregulated at early and late wounding time-points as well as between genes induced by jasmonic acid and those not induced. Expanding on what we currently know, we identified cis-elements that improved model predictions of expression clusters over known binding sites. Using a combination of genome editing, in vitro DNA-binding assays, and transient expression assays using native and mutated cis-regulatory elements, we experimentally validated four of the predicted elements, three of which were not previously known to function in wound-response regulation. Our study provides a global model predictive of wound response and identifies new regulatory sequences important for wounding without requiring prior knowledge of the transcriptional regulators.
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This content will become publicly available on June 6, 2026
Tyrosine and Phenylalanine Activate Neuronal DNA Repair but Exhibit Opposing Effects on Global Transcription and Adult Female Mice Are Resilient to TyrRS/YARS1 Depletion
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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- Award ID(s):
- 2047700
- PAR ID:
- 10600819
- Publisher / Repository:
- Wiley
- Date Published:
- Volume:
- 77
- Issue:
- 6
- Subject(s) / Keyword(s):
- aminoacyl-tRNA synthetases | amyloid beta | aromatic amino acids | DNA repair | female resilience | neuronal transcription | resilience to tau accumulation
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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