Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73

Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPΔCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPΔCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPΔCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Novel production of beta-cryptoxanthin in haskap (Lonicera caerulea subsp. edulis) hybrids : Improvement of carotenoid biosynthesis by interspecific hybridization

Carotenoids are important color pigments that contribute to human health. Haskap (Lonicera caerulea subsp. edulis), a shrub mainly distributed in Hokkaido, produces violet-blue berries low in carotenoid amount. We have conducted interspecific hybridization between Miyama-uguisukagura (Lonicera gracilipes var. glandulosa) and haskap to obtain interspecific hybrids for improving fruit quality. In this study, we compared four carotenoid concentrations in fruits using liquid chromatography/tandem mass spectrometry (LC/MS/MS) to reveal carot-enoid accumulation changes by interspecific hybridization. beta-Carotene was the main carotenoid, and the con-centration in interspecific hybrids (0.49-0.77 mg/100 g FW) was higher than Miyama-uguisukagura (0.37 mg/ 100 g FW) and haskap (0.25-0.35 mg/100 g FW). beta-Cryptoxanthin concentration was below the quantification limit in haskap strains; however, we could quantify beta-cryptoxanthin in interspecific hybrids. beta-Cryptoxanthin concentration in Miyama-uguisukagura fruits and the interspecific hybrid strain that contained higher beta-cryp-toxanthin tended to increase during maturation, although others did not increase. Our study revealed that interspecific hybridization changed carotenoid biosynthesis, increased beta-carotene, and induced the conversion of beta-cryptoxanthin to haskap. This study proposes a strategy to expand color variation by interspecific hybridization in fruit breeding programs and provides novel materials to analyze the vigor phenomenon in hybrid plants

Evaluation of Fruit Anthocyanin Composition by LC/MS in Interspecific Hybrids Between Haskap (Lonicera caerulea subsp. edulis (Turcz. ex. Herder) Hulten) and Miyama-uguisukagura (Lonicera gracilipes Miq.)

Haskap (Lonicera caerulea subsp. edulis) is a deciduous shrub that produces blue-black edible berries with a sour-sweet taste. By expanding fruit color variation, the value of agricultural products is enhanced. Interspecific hybrids were obtained from crossings between Haskap and red-fruit bearing Miyamauguisukagura (Lonicera gracilipes). The fruit color of the interspecific hybrids obtained was red-purple. Fruit color in Haskap is mainly affected by the concentration of anthocyanin. However, there are no reports on the chemical determinants of fruit color in interspecific hybrids between Haskap and Miyama-uguisukagura. We evaluated anthocyanin components in these hybrids and their parents using liquid chromatography/tandem mass spectrometry, and revealed the presence of five different kinds of anthocyanins. The major anthocyanin in interspecific hybrids and Haskap was cyanidin 3-glucoside, while in Miyama-uguisukagura, it was cyanidin 3,5-diglucoside. Some genotypes among interspecific hybrids showed higher concentrations of cyanidin 3,5-diglucoside and peonidin 3,5-diglucoside, compared with their parents. The genotypes of interspecific hybrids and the parents were evaluated by principal component analysis of anthocyanin concentration. Our study contributes to the identification of anthocyanin composition in fruits of interspecific hybrids and in expanding fruit color variation when breeding new varieties

Comparison of anthocyanin distribution in berries of Haskap (Lonicera caerulea subsp. edulis (Turcz. ex. Herder) Hulten), Miyama-uguisukagura (Lonicera gracilipes Miq.), and their interspecific hybrid using imaging mass spectrometry

Haskap (Lonicera caerulea subsp. edulis), a shrub with violet-blue fruits, is distributed mainly in Hokkaido, Japan. Miyama-uguisukagura (Lonicera gracilipes), a species related to Haskap, produces red fruits. Interspecific hybridization of Miyama-uguisukagura and Haskap was performed to introduce novel characteristics in the resulting hybrids. The shape and color of the interspecific hybrid fruits differed from those of the parent fruits. A comparison of anthocyanin distribution among these three fruit types by imaging mass spectrometry (IMS) revealed the presence of five different anthocyanins. The average cyanidin 3,5-diglucoside and peonidin 3,5diglucoside intensities in the interspecific hybrid fruit were higher than those of the parent fruits, whereas the average pelargonidin 3-glucoside, cyanidin 3-glucoside, and peonidin 3-glucoside intensities were the highest in Haskap. All anthocyanins were mainly accumulated in the inner and outer skins of Haskap and interspecific hybrid fruits, and in the skin of Miyama-uguisukagura fruits. The order of signal intensities of all anthocyanins among the three fruits was unchanged in different regions. Additionally, a comparison of IMS and LC/MS data from our previous study confirmed the possibility of comparing multiple fruits in the same plate by IMS. Thus, we elucidated anthocyanin distribution patterns of the interspecific hybrid and parent fruits by IMS