Biology subjects

Szabo, P.

Publications and source records attributed to Szabo, P..

6 recordsLinked to original sources

bioRxiv2026

One-carbon metabolism controls colorectal cancer cell state and chemosensitivity through chromatin remodeling

Folate is co-administered with fluoropyrimidines in colorectal cancer to potentiate thymidylate synthase inhibition, yet its therapeutic effects are paradoxically inconsistent across disease and treatment settings. Here we show that one-carbon metabolism remodels epithelial identity before treatment and thereby alters fluoropyrimidine response. Folate restoration shifted colorectal cancer cells along a polarized epithelial axis from a stem-like toward a differentiated state, whereas folate deprivation favored the opposite configuration. These pretreatment states differed markedly in 5-fluorouracil sensitivity. Folate restoration increased sensitivity across colorectal cancer cell lines and patient-derived organoids, whereas folate deprivation or methotrexate increased therapy-induced senescence. State-dependent sensitivity was not explained by proliferation alone, as stem-like cells were least responsive under the same conditions in which their S-phase occupancy was highest. Mechanistically, folate restoration increased methylation potential, supported EZH2-dependent H3K27me3 remodeling, reorganized chromatin accessibility and transcription-factor engagement, and reduced canonical WNT activity. In human colorectal tissue, stem-like program activity was higher and differentiation program activity lower in carcinoma than in normal mucosa, with adenomas intermediate, a pattern opposite to folate-induced remodeling. Folate is therefore not merely a cofactor for thymidylate synthase inhibition but an instructive metabolic regulator of the epithelial state that stratifies fluoropyrimidine response.

molecular biology↗

bioRxiv2025

EHMT2 Controls Neural Crest-Derived Craniofacial Development but is Dispensable in Limb Development

Post-translational modifications of histones, such as methylation of histone H3 at lysine 9 (H3K9), play critical roles in regulating chromatin structure and gene expression. EHMT2 (also called G9A), a histone methyltransferase, mediates H3K9 mono- and dimethylation and has been implicated in both transcriptional repression and context-specific gene activation. Although global knockout of the mouse Ehmt2 gene results in early embryonic lethality, tissue-specific knockouts have uncovered diverse roles in organ development. However, how EHMT2 contributes to skeletal development in a lineage-specific manner remains to be fully elucidated. Here, we investigated the role of EHMT2 in skeletal development by conditionally inactivating Ehmt2 in neural crest-derived and mesoderm-derived progenitors using Wnt1-Cre and Prx1-Cre mouse lines, respectively. Loss of Ehmt2 function in neural crest cells led to postnatal growth failure and craniofacial defects, including delayed intramembranous ossification and malformations of the jaw and cranial base. Transcriptomic analysis of neural crest cells revealed disrupted chromatin regulatory networks, reduced expression of proliferation-associated genes, and upregulation of inflammatory pathways. In contrast, inactivation of Ehmt2 in Prx1-expressing mesodermal progenitors had minimal impact on limb and cranial bone development, with no significant alterations in bone mass or osteoblast function. Together, these results reveal a lineage-specific requirement for EHMT2 in neural crest-derived skeletal tissues, suggesting that distinct progenitor populations exhibit differential dependency for bone development.

cell biology↗

bioRxiv2021

H3K9 methyltransferase EHMT2/G9a controls ERVK-driven non-canonical imprinted genes

Unlike regular imprinted genes, non-canonical imprinted genes are known to not depend on gamete-specific DNA methylation difference. Instead, the paternal allele-specific expression of these genes in the extra-embryonic lineages depends on an H3K27me3-based imprint in the oocyte, but this marking is not maintained beyond pre-implantation development. The maintenance of non-canonical imprinting corresponds to maternal allele-specific DNA methylation and paternal allele-specific H3K4me3 at their somatic DMRs, which occur at ERVK repeats. We hypothesized that EHMT2, the main euchromatic H3K9 methyltransferase, also has a role in this process. Using reciprocal mouse crosses and allele-specific RNA-seq analysis, we found that the maternal allele of each known non-canonical imprinted gene was derepressed from its ERVK promoter in the Ehmt2-/- ectoplacental cone of somite-matched 8.5 dpc embryos. In the Ehmt2-/- embryos, loss of DNA methylation accompanied the derepression of both parental alleles of those ERVK promoters. Our study identifies EHMT2 as an essential player that maintains the repressed chromosomal state in non-canonical imprinting.

genetics↗

bioRxiv2020

Decoding neurobiological spike trains using recurrent neural networks; a case study with electrophysiological auditory cortex recordings

Recent advancements in multielectrode methods and spike-sorting algorithms enable the in vivo recording of the activities of many neurons at a high temporal resolution. These datasets offer new opportunities in the investigation of the biological neural code, including the direct testing of specific coding hypotheses, but they also reveal the limitations of present decoder algorithms. Classical methods rely on a manual feature extraction step, resulting in a feature vector, like the firing rates of an ensemble of neurons. In this paper, we present a recurrent neural-network based decoder and evaluate its performance on experimental and artificial datasets. The experimental datasets were obtained by recording the auditory cortical responses of rats exposed to sound stimuli, while the artificial datasets represent preset encoding schemes. The task of the decoder was to classify the action potential timeseries according to the corresponding sound stimuli. It is illustrated that, depending on the coding scheme, the performance of the recurrent-network based decoder can exceed the performance of the classical methods. We also show how randomized copies of the training datasets can be used to reveal the role of candidate spike-train features. We conclude that artificial neural network decoders can be a useful alternative to classical population vector based techniques in studies of the biological neural code.

neuroscience↗

bioRxiv2020

Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing

Adaptive immunity and tumor-promoting inflammation exist in delicate balance in individual tumor microenvironments; however, the role of this balance in defining sensitivity and resistance to PD-1/PD-L1 blockade therapy in urothelial cancer and other malignancies is poorly understood. We pursued an unbiased systems biology approach using bulk RNA sequencing data to examine pre-treatment molecular features associated with sensitivity to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer and identified an adaptive_immune_response module associated with response and an inflammatory_response module and stromal module associated with resistance. We mapped these gene modules onto single-cell RNA sequencing data demonstrating the adaptive_immune_response module emanated predominantly from T, NK, and B cells, the inflammatory_response module from monocytes/macrophages, and the stromal module from fibroblasts. The adaptive_immune_response:inflammatory_response module expression ratio in individual tumors, reflecting the balance between antitumor immunity and tumor-associated inflammation and coined the 2IR score, best correlated with clinical outcomes and was validated in an independent cohort. Individual monocytes/macrophages with low 2IR scores demonstrated upregulation of proinflammatory genes including IL1B and downregulation of antigen presentation genes, were unrelated to classical M1 versus M2 polarization, and were enriched in pre-treatment peripheral blood from patients with PD-L1 blockade-resistant metastatic urothelial cancer. Single sentence summaryProinflammatory monocytes/macrophages, present in tumor and blood, are associated with resistance to immune checkpoint blockade in urothelial cancer.

genomics↗

bioRxiv2018

Differential DNA modification of an enhancer at the IGF2 locus affects dopamine synthesis in patients with major psychosis

Dopamine dysregulation is central to the pathogenesis of diseases with major psychosis, but its molecular origins are unclear. In an epigenome-wide investigation in neurons, individuals with schizophrenia and bipolar disorder showed reduced DNA modifications at an enhancer in IGF2, which disrupted the regulation of the dopamine synthesis enzyme tyrosine hydroxylase and striatal dopamine levels in transgenic mice. Epigenetic control of this enhancer may be an important molecular determinant of psychosis.

neuroscience↗