GDNF-inducible zinc finger protein 1 is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory region

The RET tyrosine kinase receptor and its ligand, glial cell line-derived neurotrophic factor (GDNF) are critical regulators of renal and neural development. It has been demonstrated that RET activates a variety of downstream signaling cascades, including the RAS/mitogen-activated protein kinase and phosphatidylinositol-3-kinase(PI3-K)/AKT pathways. However, nuclear targets specific to RET-triggered signaling still remain elusive. We have previously identified a novel zinc finger protein, GZF1, whose expression is induced during GDNF/RET signaling and may play a role in renal branching morphogenesis. Here, we report the DNA binding property of GZF1 and its potential target gene. Using the cyclic amplification and selection of targets technique, the consensus DNA sequence to which GZF1 binds was determined. This sequence was found in the 5′ regulatory region of the HOXA10 gene. Electrophoretic mobility shift assay revealed that GZF1 specifically binds to the determined consensus sequence and suppresses transcription of the luciferase gene from the HOXA10 gene regulatory element. These findings thus suggest that GZF1 may regulate the spatial and temporal expression of the HOXA10 gene which plays a role in morphogenesis

ゴルジノラクトンの合成研究

講演番号：4ⅢL 2

Correlated Alterations in Serotonergic and Dopaminergic Modulations at the Hippocampal Mossy Fiber Synapse in Mice Lacking Dysbindin

Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered monoaminergic modulation at the mossy fiber synapse could be a candidate pathophysiological basis for impairment of hippocampus-dependent brain functions in schizophrenia

Multi -ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10−8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.We thank the Director of Health Malaysia for supporting the work described in the South Asian (SAS) population: the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) study. The MyEIRA study was funded by grants from Ministry of Health Malaysia (NMRR-08-820-1975) and the Swedish National Research Council (DNR-348-2009-6468). The GENRA study and the CARDERA genetics cohort genotyping were funded by Versus Arthritis (grant reference 19739 to I.C.S.). The Nurses’ Health Study (NHS cohort) is funded by the National Institutes of Health (NIH) (R01 AR049880, UM1 CA186107, R01 CA49449, U01 CA176726 and R01 CA67262). The Swedish EIRA study was supported by the Swedish Research Council (to L.K., L.P. and L.A.). S.S. was in part supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kanae Foundation for the Promotion of Medical Science, Astellas Foundation for Research on Metabolic Disorders, JCR Grant for Promoting Basic Rheumatology, and Manabe Scholarship Grant for Allergic and Rheumatic Diseases. I.C.S. is funded by the National Institute for Health and Care Research (NIHR) Advanced Research Fellowship (grant reference NIHR300826). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. K.A.S. is supported by the Sherman Family Chair in Genomic Medicine and by a Canadian Institutes for Health Research Foundation Grant (FDN 148457) and grants from the Ontario Research Fund (RE-09-090) and Canadian Foundation for Innovation (33374). S.-C.B. is supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2021R1A6A1A03038899). R.P.K. and J.C.E. are funded by NIH (UL1 TR003096). C.M.L. is partly funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. T. Arayssi was partially supported by the National Priorities Research Program (grant 4-344-3-105 from the Qatar National Research Fund, a member of Qatar Foundation). M. Kerick and J.M. are funded by Rheumatology Cooperative Research Thematic Network program RD16/0012/0013 from the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). Y.O. is funded by JSPS KAKENHI (19H01021 and 20K21834), AMED (JP21km0405211, JP21ek0109413, JP21ek0410075, JP21gm4010006 and JP21km0405217), JST Moonshot R&D (JPMJMS2021 and JPMJMS2024), Takeda Science Foundation, and the Bioinformatics Initiative of Osaka University Graduate School of Medicine. Y. Kochi is funded by grants from Nanken-Kyoten, TMDU and Medical Research Center Initiative for High Depth Omics. S.R. is supported by UH2AR067677, U01HG009379, R01AR063759 and U01HG012009

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

Influence of lithium salts on the combustion characteristics of dimethyl carbonate-based electrolytes using a wick combustion method

Flammability studies of electrolytes are required for screening safer materials used in lithium-ion batteries. Besides the thermal stability, the effects of lithium salts on electrolyte combustion are important as well for fire safety of electrolytes. To clarify the influence of lithium salts on the electrolyte flammability, experimental analyses were conducted using a unique wick combustion system in conjunction with the limiting oxygen concentration (LOC) test, called wick-LOC method. The dimethyl carbonate (DMC)-based electrolytes with 1M addition of different lithium salts (LiPF6, LiBF4, and LiTFSI) were studied comparing with pure DMC and trimethyl phosphate (TMP)-added solvents. The three lithium salts gave unique and distinct flame behaviors including flame shapes, colors and the changes of wick surface until self-extinguishing. The wick-LOC results indicated a considerable flame-retardant effect of LiPF6, while other salts have minor effects on the flame extinction. Utilizing the flame spectrum and combustion residue analyses, the roles of salts during combustion were characterized. The PF6 anion played a similar role with the TMP additive in the gas phase flame inhibition. In the cases of LiPF6 and LiBF4, the solid products (LiF) accumulation blocked the fuel supply from the wick to the flame region. In the case of LiTFSI, the serious charring of the cotton wick was considered as a potential hazard on solid combustibles in the real fire scenarios