Biology subjects

Okazaki, K.

Publications and source records attributed to Okazaki, K..

7 recordsLinked to original sources

bioRxiv2026

Hydration Energetics Shape Antibody Discrimination between Sulfotyrosine and Phosphotyrosine

Chemically similar post-translational modifications can mediate distinct biological functions, but how proteins distinguish between them remains unclear. Sulfotyrosine (sTyr) and phosphotyrosine (pTyr) exemplify this problem because they have similar sizes, local geometries, and electrostatic properties but function in different biological contexts. Here, we used the monoclonal antibody PSG2, which recognizes sTyr independently of the surrounding peptide sequence, to examine how a protein distinguishes these modifications. The crystal structure of PSG2 bound to an sTyr-containing peptide revealed a deep electropositive pocket with no modeled water molecules in direct contact with the sulfate group. Gas-phase density functional theory calculations favored pTyr over sTyr, showing that direct protein-ligand interactions alone are insufficient to explain PSG2 selectivity. Explicit first-shell hydration calculations showed that pTyr has a larger desolvation penalty than sTyr, and accounting for this difference reversed the calculated energetic order. Isothermal titration calorimetry showed favorable enthalpic and entropic contributions to sTyr binding, whereas no detectable heat signal was observed for pTyr. These results show that PSG2 distinguishes sTyr from pTyr through the balance between direct protein-ligand interactions and ligand desolvation.

biophysics↗

bioRxiv2026

Chromatin landscape and epigenetic heterogeneity of acute myeloid leukemia

Acute myeloid leukemia (AML) is an aggressive hematologic cancer characterized by proliferation of immature myeloblasts. It shows profound molecular heterogeneity, which has been primarily studied through genetic abnormalities, providing the basis for disease classification, prognostication, and therapeutic choice. However, genetic factors alone may not fully explain AML pathogenesis and diversity, while leaving the role of abnormal epigenome, particularly chromatin state, largely unexplored in a large cohort of patients. Here we show that AML is classified into 16 subgroups with distinct chromatin accessibility profiles based on ATAC-seq in 1,563 AML cases, including novel AML subgroups not previously recognized in conventional genomic classifications. By integrating multi-omics analyses of genome, transcriptome, and major histone marks, we show that these epigenetic subgroups exhibit unique features in clinical presentation, gene mutations, differentiation states, gene expression, and super-enhancer profiles, which are validated across independent cohorts. Single-cell sequencing demonstrates the presence of subgroup-specific ATAC signatures that are shared by all leukemic cells, confirming the definitive role of the epigenome in the ATAC-based classification. Mechanistically, each subgroup is associated with a distinct gene regulatory network centered on key transcription factors, where subgroup-specific super-enhancers play a pivotal role. These ATAC subgroups also have prognostic significance independent of genomic classification, and help reveal unexpected drug sensitivities. In summary, ATAC-based chromatin profiling in this large sample set, combined with multi-omics data, provides new insights into AML pathogenesis beyond genomic profiling and also serves as an invaluable resource for AML research.

cancer biology↗

bioRxiv2025

Regnase-1 Promotes Tumor-Initiating Activity in Non-Small Cell Lung Cancer

Regnase-1, encoded by the ZC3H12A gene, is a well-known RNase that suppresses inflammation by degrading the mRNAs of inflammatory cytokines. However, its role in cancer pathogenesis, especially in non-small cell lung cancer (NSCLC), remains poorly understood. Through an analysis of public databases, we found that NSCLC patients with higher ZC3H12A expression levels had a worse prognosis than those with lower levels. To explore the function of Regnase-1 in NSCLC, we knocked out the ZC3H12A gene in NSCLC cell lines and compared their transcriptomes with those of parental cells. This analysis identified the SOX2 pathway as a common pathway suppressed by Regnase-1 deficiency. Consistent with the SOX2 contribution to the cancer stemness, Regnase-1 inhibition impaired oncosphere growth and tumor formation of cell lines derived from adenocarcinoma, squamous cell carcinoma and large cell carcinoma. It was also effective for NRF2-activated NSCLC cells, which are highly resistant to most of the therapeutics. Notably, post-tumorigenic suppression of Regnase-1 significantly inhibited tumor growth, suggesting that Regnase-1 could be a promising therapeutic target for post-tumorigenic treatment of NSCLC. Given recent studies describing that Regnase-1 inhibition enhances anti-cancer immunity, we propose that targeting Regnase-1 could be an ideal strategy for controlling intractable cancers by both suppressing cancer cells and activating anti-cancer immunity.

cancer biology↗

bioRxiv2021

Genome features of common vetch (Vicia sativa) in natural habitats

Wild plants are often tolerant to biotic and abiotic stresses in their natural environments, whereas domesticated plants such as crops frequently lack such resilience. This difference is thought to be due to the high levels of genome heterozygosity in wild plant populations and the low levels of heterozygosity in domesticated crop species. In this study, common vetch (Vicia sativa) was used as a model to examine this hypothesis. The common vetch genome (2n = 14) was estimated as 1.8 Gb in size. Genome sequencing produced a reference assembly that spanned 1.5 Gb, from which 31,146 genes were predicted. Using this sequence as a reference, 24,118 single nucleotide polymorphisms were discovered in 1,243 plants from 12 natural common vetch populations in Japan. Common vetch genomes exhibited high heterozygosity at the population level, with lower levels of heterozygosity observed at specific genome regions. Such patterns of heterozygosity are thought to be essential for adaptation to different environments. These findings suggest that high heterozygosity at the population level would be required for wild plants to survive under natural conditions while allowing important gene loci to be fixed to adapt the conditions. The resources generated in this study will provide insights into de novo domestication of wild plants and agricultural enhancement. HighlightSequence analysis of the common vetch (Vicia sativa) genome and SNP genotyping across natural populations revealed nucleotide diversity levels associated with native population environments.

genomics↗

bioRxiv2020

Analysis of Complex DNA Rearrangements During Early Stages of HAC Formation

Human Artificial Chromosomes (HACs) are important tools for epigenetic engineering, for measuring chromosome instability (CIN) and possible gene therapy. However, their use in the latter is potentially limited because the input HAC-seeding DNA can undergo an unpredictable series of rearrangements during HAC formation. As a result, after transfection and HAC formation, each cell clone contains a HAC with a unique structure that cannot be precisely predicted from the structure of the HAC-seeding DNA. Although it has been reported that these rearrangements can happen, the timing and mechanism of their formation has yet to be described. Here we synthesized a HAC-seeding DNA with two distinct structural domains and introduced it into HT1080 cells. We characterized a number of HAC-containing clones and subclones to track DNA rearrangements during HAC establishment. We demonstrated that rearrangements can occur early during HAC formation. Subsequently, the established HAC genomic organization is stably maintained across many cell generations. Thus, early stages in HAC formation appear to at least occasionally involve a process of DNA shredding and shuffling that resembles chromothripsis, an important hallmark of many cancer types. Understanding these events during HAC formation has critical implications for future efforts aimed at synthesizing and exploiting synthetic human chromosomes.

synthetic biology↗

bioRxiv2020

Enhancer Remodeling Promotes Tumor-Initiating Activity in NRF2-Activated Non-Small Cell Lung Cancers

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we found that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs was found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which NOTCH3 enhancer was shown to be critical for the promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

cancer biology↗

bioRxiv2019

Evaluation of radioprotective effect of chickpea (Cicer arietinum) in the survival of Lasioderma serricorne (Fabricius, 1972) (Coleoptera, Anobiidae) irradiated with 60Co

We investigated the presence of natural radioprotectors in food using a new technical modality that utilizes the insect Lasioderma serricorne as a radiosensitivity bioindicator to check radioprotection properties in minimally processed chickpeas. The insects were obtained from the entomological biotherium of the Laboratory of Radiobiology and Environment of CENA-USP. They were fed with an experimental diet and just when the first generation hatched completely, the experiments were conducted. The randomly chosen control diet, consisted of three parts of wheat germ, one part of brewers yeast, and a slice of French bread toasted in an oven previously set up for humidity control. The diet of chickpeas consists only of whole grains crushed in a mechanical grinder to obtain flour. The result was significant for the survival of insects (p<0.0001) reared on a diet of chickpeas compared to those reared on control diet irradiated with gamma rays from 60Co in the range of 5.0 to 1500 Gy. We presented statistical evidence that the chickpea diet has radioprotective properties in the insect for gamma rays.\n\nSUMMARY STATEMENTThe study is important because it shows that chickpea has protective properties against ionizing radiation, how to act against its biological effects and minimize them.

biophysics↗