Biology subjects

Uranishi, K.

Publications and source records attributed to Uranishi, K..

5 recordsLinked to original sources

bioRxiv2023

Ablation of Max expression induces meiotic onset in sexually undifferentiated germ cells

Meiosis is a specialized type of cell division that occurs only in germ cells physiologically. We have previously demonstrated that MYC-associated factor X (MAX) is involved in blocking ectopic and precocious meiotic onsets in embryonic and germline stem cells, respectively, as a central component of the PRC1 subtype PRC1.6. In this study, we investigated the role of the Max gene in germ cells in vivo. Our data revealed that mitotically active germ cell-specific disruption of Max was coupled to meiotic onset in male and female germ cells. However, such Max-null germ cells did not undergo meiotic processes progressively, but were stalled at its relatively early stages and eventually eliminated by apoptosis. Our data also revealed that Max, which is generally known as an obligate heterodimerization partner for MYC and MXD transcription factors, showed high expression in sexually undifferentiated male and female germ cells, but female germ cells exhibited an abrupt decline in its expression at the timing of or immediately prior to physiological meiotic onset. Moreover, computational analyses identified the regulatory region that supported high levels of Max expression in sexually undifferentiated germ cells.

developmental biology↗

bioRxiv2023

Similarity and dissimilarity in alteration of gene expression profile associated with inhalational anesthesia between sevoflurane and desflurane

Although sevoflurane is the most commonly used inhalational anesthetic agent, the popularity of desflurane is increasing to a similar level. The main beneficial property of desflurane is the relatively fast emergence of the patient from the anesthetic state after halting its supply compared with anesthesia using other anesthetic agents. However, there has been no comprehensive comparison of the effects of these two anesthetic agents on alterations in liver gene expression profiles in animals, including humans, to assess the levels of hepatotoxicity that is induced at least in some extent by inhalational anesthesia. Thus, we compared alterations in the global gene expression profiles in the livers of rats subjected to inhalational anesthesia by sevoflurane or desflurane by a next-generation sequencing method. Our data revealed that both anesthetic agents significantly activated a similar set of genes including those related to drug metabolism and circadian rhythm. Furthermore, many genes downregulated by sevoflurane were also downregulated by desflurane. However, many of the genes related to the cholesterol biosynthetic process were specifically repressed by sevoflurane, but not by desflurane.

molecular biology↗

bioRxiv2022

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer

BackgroundFluoropyrimidine-based adjuvant chemotherapy is globally recommended for postoperative stage III colon cancer and high-risk stage II patients. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, a recurrence-prevention biomarker of adjuvant chemotherapy for colorectal cancer is necessary for providing such treatments to appropriate patients. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between the single-nucleotide variants of autophagy-related genes and recurrence rates to identify the recurrence-prevention biomarkers of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer patient relapse rates. ResultsWe detected 560 single-nucleotide variants or insertions/deletions in the target region. The results of Fishers exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single- nucleotide variants (c.1018G>A [p < 0.005] or c.1562A>C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. ConclusionsThe two single-nucleotide variants of this mitophagy-related gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

cancer biology↗

bioRxiv2020

Identification of germ cell-specific Mga variant mRNA that promotes meiotic entry via impediment of a non-canonical PRC1

Transition from mitosis to meiosis in cell division is a fundamental process of gametogenesis. This transition is thought to be largely controlled by the exchange of relative dominance between positive and negative regulation by the retinoic acid/Stra8 signal cascade and a non-canonical PRC1 (PRC1.6), respectively. We have previously demonstrated that germ cells have transcriptionally and/or post-translationally reduced levels of MAX, a component of PRC1.6, immediately prior to meiotic onset, leading to alleviation of the negative effect of PRC1.6 against meiotic onset. Here, we found that germ cells produced Mga variant mRNA bearing a premature termination codon (PTC) during meiosis as an additional mechanism to impede the function of PRC1.6. Our data indicated that spermatocytes and/or round spermatids produced an anomalous MGA protein lacking the bHLHZ domain from the variant mRNA and therefore functioned as a dominant negative regulator of PRC1.6 by exquisitely using their inefficient background of PTC-mediated nonsense-mediated mRNA decay. Thus, our data indicate that meiotic onset of male germ cells is controlled in a multi-layered manner in which both MAX and MGA, which constitute the core of PRC1.6 by their interaction, are at least used as targets to deteriorate the integrity of the complex to ensure initiation of meiosis. Significance StatementPRC1.6, a non-canonical PRC1, functions as a strong blocker of meiotic onset. Therefore, germ cells need to alleviate the function of the complex as a prerequisite for meiotic onset. The MGA/MAX heterodimer not only constitutes a core of PRC1.6, but also confers direct DNA-binding activity to the complex. We have previously demonstrated that germ cells reduce Max amounts prior to meiotic onset to inactivate PRC1.6. In this study, we explored the possibility of an additional molecular mechanism that promotes meiotic onset via impediment of PRC1.6 functions as a safeguard system. Here, we demonstrate that meiotic germ cells specifically generate variant Mga mRNA by alternative splicing, which leads to production of a dominant negative regulator of PRC1.6.

developmental biology↗

bioRxiv2020

Two DNA binding domains of Mga act in combination to suppress ectopic activation of meiosis-related genes in mouse embryonic stem cells

Mouse embryonic stem cells (ESCs) have high potential for meiotic entry, like germ cells. Although the physiological meaning of this potential is not known, it is certain that a rigid safeguarding system is required to prevent ectopic onset of meiosis. PRC1.6, a non-canonical PRC1, is known for its suppression of precocious and ectopic meiotic onset in germ cells and ESCs, respectively, in which MGA has important roles in DNA binding as well as in constructing the complex as a scaffolding component. As a salient feature, MGA bears two distinct DNA-binding domains termed bHLHZ and T-box. However, how these features contribute to the functions of PRC1.6, particularly in the repression of meiotic genes, remains largely obscure. Here, we demonstrated that both DNA binding domains of Mga repress distinct sets of genes in murine ESCs, and substantial numbers of meiosis-related genes are included in both gene sets. In addition, our data demonstrated that both DNA binding domains of Mga, in particular bHLHZ, are crucially involved in repressing the expression of Meiosin, which plays essential roles in meiotic entry in collaboration with Stra8, revealing at least part of the molecular mechanisms that link negative and positive regulation of meiotic onset.

cell biology↗