Biology subjects

Akagi, K.

Publications and source records attributed to Akagi, K..

8 recordsLinked to original sources

bioRxiv2024

SL/Kh Pre-B Lymphomas Originate in the Thymus and are a Model for Primary Mediastinal (Thymic) Large B-Cell Lymphoma

SL/Kh mice develop a high frequency of retrovirally-induced pre-B lymphomas at 3-6 months of age. They also exhibit an abnormal transient expansion of pre-B cells in the bone marrow, although the relevance of this expansion for lymphomagenesis has remained unclear. Here, we use a dual approach that combines pathology with flow cytometry to more fully characterize the nature and origin of SL/Kh lymphomas. Unexpectedly, our studies showed that SL/Kh lymphomas arise from a rare population of pro/pre-B cells in the thymus. We also identified a 10-fold reduction in Notch1 expression in SL/Kh thymic T cells that is associated with a block in early T cell development, a reduction in the number of thymic T cells with age, and an expansion of thymic pro/pre-B cells. This phenotype is consistent with previous studies showing that Notch1 signaling is essential for lymphoid progenitors to undergo T cell commitment and for suppressing B cell development in the thymus. We propose that this developmental defect provides a niche for early B cells to accumulate in the thymus, which, when combined with subsequent retroviral insertional mutagenesis, results in the induction of pre-B lymphomas that originate in the thymus. This is also consistent with our analysis of the genes insertionally mutated in SL/Kh lymphomas, which shows that many function in signaling pathways such as JAK/STAT and RAS/MAPK/ERK that are commonly deregulated in B-cell lymphomas. Primary human mediastinal large B-cell lymphoma (MLBCL) is another lymphoma that is derived from thymic B cells, although virtually nothing is known about the cause of this rare disease. Our studies provide new insights into an underappreciated class of B-cell lymphomas and a mouse model for the study of MLBCL.

pathology↗

bioRxiv2024

A chromosome-level genome assembly of the Hispid cotton rat (Sigmodon hispidus), a model for human pathogenic virus infections

BackgroundThe cotton rat (Sigmodon hispidus), a rodent species native to the Americas, has emerged as a valuable laboratory model of infections by numerous human pathogens including poliovirus and respiratory syncytial virus (RSV). ResultsHere we report the first reference assembly of the cotton rat genome organized at a chromosomal level, providing annotation of 24,878 protein-coding genes. Data from PCR-free whole genome sequencing, linked-read sequencing and RNA sequencing from pooled cotton rat tissues were analyzed to assemble and annotate this novel genome sequence. Spectral karyotyping data using fluorescent probes derived from mouse chromosomes facilitated the assignment of cotton rat orthologs to syntenic chromosomes, comprising 25 autosomes and a sex chromosome in the haploid genome. Comparative phylome analysis revealed both gains and losses of numerous genes including immune defense genes against pathogens. We identified thousands of recently retrotransposed L1 and SINE B2 elements, revealing widespread genetic innovations unique to this species. ConclusionsWe anticipate that annotation and characterization of the first chromosome-level cotton rat genome assembly as described here will enable and accelerate ongoing investigations into its host defenses against viral and other pathogens, genome biology and mammalian evolution.

genomics↗

bioRxiv2023

HOIL-1L deficiency induces cell cycle alteration which causes immaturity of myocyte and fibrogenesis

HOIL-1L deficiency was recently reported to be one of the causes of myopathy and dilated cardiomyopathy (DCM). However, the mechanisms by which myopathy and DCM develop have not been clearly elucidated. Here, we sought to elucidate these mechanisms using the murine myoblast cell line C2C12 and disease-specific human induced pluripotent stem cells (hiPSCs). Myotubes were differentiated from control and HOIL-1L-KO C2C12 cells. Cardiomyocytes (CMs) were differentiated from control and patient-derived hiPSCs. We investigated the impact of HOIL-1L on differentiation of myotubes and CMs. Myotubes differentiated from HOIL-1L-KO C2C12 cells exhibited deteriorated differentiation and mitotic cell accumulation. CMs differentiaed from patient-derived hiPSCs had an abnormal morphology with a larger size and were excessively multinucleated compared with CMs differentiaed from control hiPSCs. Further analysis of hiPSC- derived CMs showed that HOIL-1L deficiency caused cell cycle alteration and mitotic cell accumulation. These results were supported by RNA sequencing of C2C12 cell-derived myotubes. In addition, SerpinE2, a cardiac fibrogenesis gene, was significantly upregulated in CMs differentiaed from patient-derived hiPSCs. These results demonstrate that abnormal cell maturation and fibrosis possibly contribute to the development of DCM and myopathy. In conclusion, HOIL-1L is an important intrinsic regulator of cell cycle-related myotube and CM maturation and cell proliferation.

cell biology↗

bioRxiv2023

Effectiveness of heat tolerance rice cultivars in preserving grain appearance quality under high temperatures - A meta-analysis

BackgroundClimate change, particularly rising temperatures, negatively affects rice grain quality, increasing chalky grain percentage (CG) and hampering rice grade and price. Heat-tolerant cultivars have been bred and released since the 2000s, but the effectiveness of heat tolerance in reducing the occurrence of CG has yet to be quantified. ObjectivesThis study aimed to measure the effectiveness of breeding for better heat tolerance in reducing the negative impact of high temperatures on rice quality. MethodsThrough a systematic literature search, we developed a dataset including 1297 field observations covering 48 cultivars from five different heat tolerant ranks (HTRs) at 44 sites across Japan. A linear mixed-effect model (LME) and a random forest model (RF) were fitted to the data to analyze the effect of HTR and climatic factors such as the cumulative mean air temperature above 26 {degrees}C (TaHD), mean solar radiation, and mean relative humidity for 20 days after heading on CG. ResultsThe LME model explained 63 % of the variation with a 14% RMSE. The RF partial dependence plot revealed that the logit-transformed CG response to climate factors was linear, supporting the assumption of LME. The statistical analysis showed that CG increased as a function of TaHD (P < 0.001), with significant differences among HTRs (P < 0.001). The strongest effect of TaHD was obtained for the lowest HTR and was found to decrease with increasing HTR. CG also increased with higher relative humidity (P < 0.001) and solar radiation (P < 0.01). Based on our modeling, we estimated that as TaHD increased from 20 to 80 {degrees}Cd (equivalent to a mean temperature increase from 27 {degrees}C to 30 {degrees}C), CG increased by 66 % points (difference in CG) for cultivars with the lowest HTR, 45 % points for cultivars with an intermediate HTR, and 19 % points for cultivars with the highest HTR. Raising HTR by just one step (from intermediate to moderately tolerant) is projected to increase the proportion of first-grade rice at a grain-filling temperature of 27 {degrees}C, but tolerance levels need to be improved further in case of stronger warming. ConclusionsThe effect of high temperatures on CG was highly dependent on the cultivars HTR. Improvements in HTR effectively reduce the negative impacts of high temperatures on rice grain quality. SignificanceHeat-tolerant cultivars are projected to suppress the prevalence of CG more than threefold compared with heat-sensitive cultivars when grain-filling temperature increases from 27 to 30 {degrees}C.

plant biology↗

bioRxiv2022

Intratumoral heterogeneity and clonal evolution induced by HPV integration

The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed a unique form of structural variation, i.e., heterocateny, characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoint sequences shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. The data indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.

cancer biology↗

bioRxiv2021

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes, but the impacts of integration in tumorigenesis remain unclear. Analysis of 105 HPV-positive oropharyngeal cancers by whole genome sequencing detects viral integration in 77%, revealing five statistically significant integration hotspots near genes that regulate epithelial stem cell maintenance (i.e. SOX2, TP63, FGFR, MYC) and immune evasion (i.e. CD274). Somatic hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with local density of HPV integrants. Genes expressed at extreme outlier levels are increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking and/or de novo expression of noncoding or imprinted genes. We conclude that HPV integration contributes substantively to cancer development by causing extensive disruption of host genome structure and gene expression.

genomics↗

bioRxiv2020

Population-wide Screening for Germline Variants of Hereditary Cancer Genes in 12K Unselected Japanese Colorectal Cancers and 27K Controls

Background & AimsColorectal cancer (CRC) is one of the most common cancers in Western countries and Japan. Currently, a few % of CRCs can be attributed to recognizable hereditary germline variants of known CRC susceptibility genes, predominantly the DNA mismatch repair genes. To establish a universal screening strategy for hereditary CRCs, it is necessary to explore the prevalence of hereditary CRC and pathogenic variants of multiple cancer-predisposing genes in non-European populations. MethodsWe analyzed the coding regions of 27 cancer-predisposing genes, including mismatch repair genes, APC, and BRCA1/2, in 12,503 unselected Japanese CRC patients and 23,705 controls aged [≥] 60 years without any personal or family history of cancer by target sequencing and genome-wide SNP chip data. Their clinical significance was assessed using ClinVar and the guidelines by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). ResultsWe identified 4,804 variants in the 27 genes and annotated them as 397 pathogenic variants, 941 benign variants, and 3,466 variants of uncertain significance, of which 43.6% were registered in neither ClinVar nor dbSNP. In total, 3.3% of the unselected CRC patients and 1.5% of the controls had a pathogenic variant of the 27 genes. The pathogenic variants of MSH2 (odds ratio (OR) =18.1), MLH1 (OR=8.6), MSH6 (OR=4.9), APC (OR=49.4), BRIP1 (OR=3.6), BRCA1 (OR=2.6), BRCA2 (OR=1.9), and TP53 (OR=1.7) were significantly associated with CRC development in the Japanese population (P-values < 0.01, FDR<0.05). Furthermore, we confirmed copy number variants (CNVs) of MSH2/EPCAM, MLH1, and APC by multiplex ligation-dependent probe amplification (MLPA) and quantitative PCR in this cohort (n = 23), including whole gene duplications of MSH2 and APC. These pathogenic variants were significantly associated with the diagnostic age and personal/family history of other types of cancer. In total, at least 3.5% of the Japanese CRC population had a pathogenic variant or CNV of the 27 cancer-predisposing genes. ConclusionsThis is the largest study of CRC heredity in the Asian population and would contribute to the development of guidelines for genetic testing and variant interpretation for heritable CRCs. Universal screening for CRC risk should be assessed in multiple genes, including BRCA1/2 and BRIP1. These data would facilitate risk assessment of cancer and optimize the screening strategy.

genetics↗

bioRxiv2019

Musashi expression in intestinal stem cells attenuates radiation-induced decline in intestinal homeostasis and survival in Drosophila

Exposure to genotoxic stress by environmental agents or treatments, such as radiation therapy, can diminish health span and accelerate aging. We have developed a Drosophila melanogaster model to study the molecular effects of radiation-induced damage and repair. Utilizing a quantitative intestinal permeability assay, we performed an unbiased GWAS screen (using [~]150 strains from the DGRP reference panel) to search for natural genetic variants that regulate radiation-induced gut permeability. From this screen, we identified the RNA binding protein, Musashi (msi).Msi overexpression promoted intestinal stem cell proliferation, which increased survival after irradiation and rescued radiation-induced gut permeability. We identified that a novel role of Msi in ISC proliferation a novel role for Msi in enhancing ISC function following radiation-induced gut damage, which identifies Msi as a potential therapeutic target.

molecular biology↗