Biology subjects

Tanizawa, H.

Publications and source records attributed to Tanizawa, H..

7 recordsLinked to original sources

bioRxiv2025

Senotherapeutic potential against xeroderma pigmentosum

Xeroderma pigmentosum (XP) is an inherited photoaging syndrome caused by mutations in genes involved in the nucleotide excision repair (NER) pathway. XP patients exhibit hypersensitivity to ultraviolet (UV) radiation, leading to accelerated skin aging and requiring lifelong sun avoidance. Here, we demonstrate that UV-induced DNA damage triggers cellular senescence and up-regulates senescence-associated secretory phenotype (SASP) genes in melanocytes derived from an XP patient. To explore the potential therapeutics for XP, we developed a cisplatin-based drug screening system and identified JAK inhibitors and curcuminoids as promising senomorphic agents. In addition, two classes of senolytic agents, BCL-2-like protein inhibitors and HSP90 inhibitors, effectively eliminate senescent melanocytes. Further analysis demonstrates that senomorphic treatment effectively counteracts senescence and reduces SASP gene expression in XP-derived melanocytes. Moreover, genes in senescence-related pathways, including the JAK/STAT, Type I interferon (IFN-I), and PI3K/AKT pathways, which are activated by both UV irradiation and cisplatin treatment, are down-regulated by senomorphic treatment. This study highlights a potential senotherapeutic strategy for XP, which may help alleviate photoaging symptoms in XP patients.

cell biology↗

bioRxiv2024

Local chromatin decompaction shapes mitotic chromosome landscape

Unregulated activation of transcription on mitotic chromosomal arms can be detrimental to faithful chromosome segregation1-3, although a subset of genes are up-regulated during mitosis4, raising the question as to how gene activation is coordinated in the context of mitotic chromosome reorganization. Here we investigate the fine structure of mitotic chromosomes in fission yeast Schizosaccharomyces pombe and reveal that intense decompaction of local chromatin upon mitotic gene activation helps shape the mitotic chromosome landscape. More specifically, we show that binding of mitosis-specific transcription factors, Ace2 and MluI binding factor (MBF)5,6, to gene promoters followed by transcriptional elongation can locally induce chromatin decompaction during mitosis. Interestingly, local decompaction-competent genes can establish chromatin boundaries that demarcate long-range contact domains, indicating tight coupling between local and global genome organizations. Furthermore, efficient local decompaction requires enough transcriptional elongation distance and histone removal, providing a mechanistic insight into the decompaction-associated domain boundary formation. Given that the demarcation of large, self-associating domains is critical for faithful chromosome segregation7, we propose that decompaction-competent genes can be a key determinant of mitotic chromosome configuration, thereby underpinning the maintenance of genome integrity over generations, and thus their distribution along chromosomes can be subject to evolutionary selection.

molecular biology↗

bioRxiv2024

A role for condensin-mediator interaction in mitotic chromosomal organization

Eukaryotic genomes are organized by condensin into 3D chromosomal architectures suitable for chromosomal segregation during mitosis. However, molecular mechanisms underlying the condensin-mediated chromosomal organization remain largely unclear. Here, we investigate the role of newly identified interaction between the Cnd1 condensin and Pmc4 mediator subunits in fission yeast, Schizosaccharomyces pombe. We develop a condensin mutation, cnd1-K658E, that impairs the condensin-mediator interaction and find that this mutation diminishes condensin-mediated chromatin domains during mitosis and causes chromosomal segregation defects. The condensin-mediator interaction is involved in recruiting condensin to highly transcribed genes and mitotically activated genes, the latter of which demarcate condensin-mediated domains. Furthermore, this study predicts that mediator-driven transcription of mitotically activated genes contributes to forming domain boundaries via phase separation. This study provides a novel insight into how genome-wide gene expression during mitosis is transformed into the functional chromosomal architecture suitable for chromosomal segregation. O_FIG O_LINKSMALLFIG WIDTH=189 HEIGHT=200 SRC="FIGDIR/small/600663v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@488ab5org.highwire.dtl.DTLVardef@8a7a73org.highwire.dtl.DTLVardef@16d416eorg.highwire.dtl.DTLVardef@1e2d3db_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG In BriefMitotic chromosomes are organized by condensin into an architecture suitable for their segregation, although molecular mechanisms underlying how condensin assembles the functional chromosomal architecture remain unclear. This study with the fission yeast model organism shows that the protein interaction between condensin and mediator is involved in chromosomal segregation by forming a mitotic chromosomal architecture. A similar mechanism involving the condensin-mediator interaction is likely conserved in human cells, implying the evolutionary conservation of this mechanism. HighlightsO_LIThe Cnd1 condensin subunit interacts with the Pmc4 mediator component in fission yeast. C_LIO_LIThe condensin-mediator interaction is required to recruit condensin to highly transcribed and mitotically activated genes. C_LIO_LIThe condensin-mediator interaction is required to form chromatin domains during mitosis. C_LIO_LIMediator participates in the boundary formation of mitotic chromatin domains. C_LI

genomics↗

bioRxiv2023

Chemo-senolytic therapeutic potential against angiosarcoma

Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

cancer biology↗

bioRxiv2021

Rec8 cohesin-mediated loop-axis chromatin architecture is required for meiotic recombination

During meiotic prophase, cohesin-dependent axial structures are formed in the synaptonemal complex (SC). However, the functional correlation between these structures and cohesion remains elusive. Here, we examined the formation of cohesin-dependent axial structures in the fission yeast Schizosaccharomyces pombe. This organism forms atypical SCs composed of linear elements (LinEs) resembling the lateral elements of SC but lacking the transverse filaments. Hi-C analysis using a highly synchronous population of meiotic S. pombe cells revealed that the axis-loop chromatin structure formed in meiotic prophase was dependent on the Rec8 cohesin complex. In contrast, the Rec8-mediated formation of the axis-loop structure occurred in cells lacking components of LinEs. To dissect the functions of Rec8, we identified a rec8-F204S mutant that lost the ability to assemble the axis-loop structure without losing cohesion of sister chromatids. This mutant showed defects in the formation of the axis-loop structure and LinE assembly and thus exhibited reduced meiotic recombination. Collectively, our results demonstrate that the Rec8-dependent axis-loop structure provides a structural platform essential for LinE assembly, facilitating meiotic recombination of homologous chromosomes, independently of its role in sister chromatid cohesion.

cell biology↗

bioRxiv2021

The ACF Chromatin Remodeling Complex is Essential for Polycomb Repression

Establishing and maintaining appropriate gene repression is critical for the health and development of multicellular organisms. Histone H3 lysine 27 (H3K27) methylation is a chromatin modification associated with repressed facultative heterochromatin, but the mechanism of this repression remains unclear. We used a forward genetic approach to identify genes involved in transcriptional silencing of H3K27-methylated chromatin in the filamentous fungus Neurospora crassa. We found that the N. crassa homologs of ISWI (NCU03875) and ACF (NCU00164) are required for repression of a subset of H3K27-methylated genes and that they form an ACF chromatin remodeling complex. This N. crassa ACF complex interacts with chromatin throughout the genome, yet association with facultative heterochromatin is specifically promoted by the H3K27 methyltransferase, SET-7. H3K27-methylated genes that are upregulated when iswi or acf1 are deleted show a downstream shift of the +1 nucleosome, suggesting that proper nucleosome positioning is critical for repression of facultative heterochromatin. Our findings support a direct role for the ACF complex in Polycomb repression.

genetics↗

bioRxiv2020

CTCF-mediated Genomic Effects of BART Region on Epstein-Barr Virus Chromatin 3D Structure in Gastric Carcinoma Cells

EBV latent infection in gastric carcinoma (GC) cells is characterized by distinct viral gene expression programs. CCCTC-binding factor (CTCF) is a chromatin structural factor that has been involved in coordinated chromatin interactions between multiple loci of Epstein-Barr virus (EBV) genes. Here, we investigate the role of CTCF in regulating EBV gene expression and chromosome conformation in model of EBV-associated gastric carcinoma (EBVaGC). Chromatin immunoprecipitation followed by sequencing (ChIP-seq) against CTCF revealed 16 CTCF binding sites (BS) in EBV genome of EBVaGC, SNU719 cells. Among the CTCF BSs, one site named as BARTp (BamHI A right transcript promoter) CTCF BS is located at upstream of 11.8-kb BART region (EBV genome: 139724-151554) and was not yet defined its biological functions in EBV life cycle. EBV BART encodes a complex miRNA cluster of highly spliced transcripts that is implicated in EBV cancer pathogenesis. This present study investigated the functional role of the CTCF binding site at BARTp (BARTp CTCF BS) in regulating EBV gene transcription and EBV three-dimensional (3D) genome structure as DNA loop maker. Circular chromatin confirmation capture (4C)-seq and chromatin confirmation capture (3C)-semi-quantitative(sq)PCR assays using SNU719 cells revealed that BARTp CTCF BS interacts with CTCF BSs of LMP1/2, Cp/OriP, and Qp in EBV genome. We generated mutations in BARTp CTCF BS (S13) in bacmids with (BART+) or without (BART-) the 11.8-kb BART transcript unit (B(+/-)). ChIP-qPCR assay demonstrated that CTCF binding was ablated from BARTp in EBV B(+/-) S13- genomes (mutant S13), elevated at several other sites such as LMP1, OriP, and Cp in EBV B(-) (BART-) S13- genome, and decreased at the same sites in EBV B(+) S13- genome. Infection assay showed that BARTp CTCF BS mutation reduced infectivity, while BART transcript deletion has no detectable effects. Gene expression tests showed that EBNA1 was highly downregulated in B(+/-) S13- EBVs related to B(+/-) S13+ EBVs (wild-type S13). LMP1 and BZLF1 were more downregulated in B(-) S13- EBV than B(+) S13- EBV. Taken together, these findings suggest that the CTCF binding and BART region contribute to EBV 3D genome structure via a cluster of DNA loops formed by BARTp CTCF BS (S13) and are important for coordinated viral gene expression and EBV infectivity.

microbiology↗