Biology subjects

Endo, Y.

Publications and source records attributed to Endo, Y..

22 records · Page 2Linked to original sources

bioRxiv2020

Genetic signatures of evolution of the pluripotency gene regulating network across mammals

Mammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics, but we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we applied a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We found evolutionary conservation in JAK-STAT and PI3K-Akt signaling pathways, suggesting equivalent capabilities in self-renewal and proliferation of mammalian PSCs. On the other hand, we discovered rapid evolution of the downstream targets of the core regulatory circuit, providing insights into variations of characteristics. Our data indicate that the variations in the PSCs characteristics may be due to positive selections in the downstream targets of the core regulatory circuit. We further reveal that positively selected genes can be associated with species unique adaptation that is not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs.

evolutionary biology↗

bioRxiv2019

Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline

Ryanodine receptor type I-related myopathies (RYR1-RMs) represent the largest group of non-dystrophic myopathies. RYR1-RMs are associated with severe disabilities and early mortality; despite these facts, there are currently no available treatments. The goal of this study was to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a novel discovery pipeline using nematode, zebrafish, and mammalian cell models of the disease. We first performed large-scale drug screens in C. elegans and zebrafish. 74 positive hits were identified in C. elegans, while none were uncovered in the zebrafish. Targeted testing of these hits in zebrafish yielded positive results for two compounds. We examined these compounds using newly created Ryr1 knockout C2C12 cells, and found that p38 inhibition impaired caffeine-induced Ca2+ release. Lastly, we tested one p38 inhibitor in myotubes from Ryr1Y524S/+ (YS) mice, and demonstrated that it blunts the aberrant temperature-dependent increase in resting Ca2+ in these cells. In all, we developed a unique platform for RYR1-RM therapy development that is potentially applicable to a broad range of neuromuscular disorders.

genetics↗

bioRxiv2019

Aberrant expression of the COX2/PGE2 axis is induced by activation of the RAF/MEK/ERK pathway in BRAFV595E canine urothelial carcinoma

Cancer-promoting inflammation is an important event in cancer development. The cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) axis is a prominent inducer of inflammation. Canine urothelial carcinoma (cUC) uniquely overexpresses PGE2 and is often managed well with COX inhibitor monotherapy. In most cases, cUC tissue harbours homologous human BRAFV600E mutation, which causes aberrant activation of the RAF/MEK/ERK pathway in human cancer. However, mechanisms underlying aberrant PGE2 production and the importance of the BRAF mutation remain unclear. We show that activation of the RAF/MEK/ERK pathway in BRAF mutant cUC cells leads to COX2 overexpression and PGE2 production. Drug screening revealed that treatment with inhibitors of the arachidonic acid cascade (FDR<0.086), RAF/MEK/ERK pathway (FDR<0.067), and p38/JNK pathway (FDR<0.067) significantly reduced PGE2 production in cUC cells. We also validated the association between RAF/MEK/ERK pathway activation and COX2/PGE2 overexpression in BRAF mutant cUC cells using protein detection techniques. In histochemical analysis, BRAF mutant cUC tissue showed higher COX2 expression. Therefore, the driver mutation in the BRAF gene probably promotes tumour-promoting inflammation. These findings would benefit dogs suffering from cUC and can be extrapolated to human cancer. Finally, cUC can serve as a valuable model to elucidate the association between driver mutations and tumour-promoting inflammation.

cancer biology↗

bioRxiv2018

Genetic Signatures of Lipid Metabolism Evolution in Cetacea

In mammalian evolutionary history, Cetacea (whales, dolphins, and porpoises) achieved astonishing success by adapting to an aquatic environment. One unique characteristic of cetaceans, contributing to this adaptive success, is efficient lipid utilization. Here we report comparative genetic analysis of aquatic and terrestrial Cetartiodactyla using 144 genes associated with lipid metabolism. We analyzed mutation rate, amino acid substitution, and metabolic pathways using genetic data publicly available. Our test detected 18 positively selected genes in Cetacea compared to 13 in Bovidae with little overlap between the lineages. We identified lineage-specific patterns of amino acid substitutions and functional domain that were mutually exclusive between cetaceans and bovids, supporting divergent evolution of lipid metabolism since the divergence of these taxa from a common ancestor. Moreover, a pathway analysis showed that the identified genes in cetaceans were associated with lipid digestion, lipid storage, and energy producing pathways. This study emphasizes the evolutionary context of lipid metabolism modification of cetaceans and provides a foundation for future studies of elucidating the adapted biological mechanisms of cetacean lipid metabolism and a framework for incorporating ecological context into studies aimed at investigating adaptive evolution.

evolutionary biology↗