55 research outputs found

    CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription

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    <p>Abstract</p> <p>Background</p> <p>Previous studies have demonstrated tissue-specific regulation of the rhythm of circadian transcription, suggesting that transcription factor complex CLOCK/BMAL1, essential for maintaining circadian rhythm, regulates transcription in a tissue-specific manner. To further elucidate the mechanism of the cell type-specific regulation of transcription by CLOCK/BMAL1 at the molecular level, we investigated roles of CBP/p300 and tissue-specific cofactors in CLOCK/BMAL1-mediated transcription.</p> <p>Results</p> <p>As shown previously, CBP/p300 stimulates CLOCK/BMAL1-mediated transcription in COS-1 cells. However, CBP/p300 repressed CLOCK/BMAL1-mediated transcription in NIH3T3 cells and knockdown of CBP or p300 expression by siRNA enhanced this transcription. Studies using GAL4-fusion proteins suggested that CBP represses CLOCK/BMAL1-mediated transcription by targeting CLOCK. We further investigated mechanisms of this cell type-specific modulation of CLOCK/BMAL1-mediated transcription by CBP by examining roles of co-repressor HDAC3 and co-activator pCAF, which are highly expressed in NIH3T3 and COS cells, respectively. CBP repressed CLOCK/BMAL1-mediated transcription in COS-1 cells when HDAC3 was overexpressed, but activated it in NIH3T3 cells when pCAF was overexpressed. CBP forms a complex with CLOCK by interacting with HDAC3 or pCAF; however, direct interaction of CBP with CLOCK was not observed.</p> <p>Conclusion</p> <p>Our findings indicate possible mechanisms by which CBP/p300 tissue-specifically acts cooperatively with pCAF and HDAC3 either as a co-activator or co-repressor, respectively, for CLOCK/BMAL1.</p

    Environmental impact on star-forming galaxies in a z0.9z \sim 0.9 cluster during course of galaxy accretion

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    Galaxies change their properties as they assemble into clusters. In order to understand the physics behind that, we need to go back in time and observe directly what is occurring in galaxies as they fall into a cluster. We have conducted a narrow-band and JJ-band imaging survey on a cluster CL1604-D at z=0.923z=0.923 using a new infrared instrument SWIMS installed at the Subaru Telescope. The narrow-band filter, NB1261, matches to Hα\alpha emission from the cluster at z=0.923z=0.923. Combined with a wide range of existing data from various surveys, we have investigated galaxy properties in and around this cluster in great detail. We have identified 27 Hα\alpha emitters associated with the cluster. They have significant overlap with MIPS 24μ\mum sources and are located exclusively in the star forming regime on the rest-frame UVJUVJ diagram. We have identified two groups of galaxies near the cluster in the 2D spatial distribution and the phase-space diagram, which are likely to be in-falling to the cluster main body. We have compared various physical properties of star forming galaxies, such as specific star formation rates (burstiness) and morphologies (merger) as a function of environment; cluster center, older group, younger group, and the field. As a result, a global picture has emerged on how the galaxy properties are altered as they assemble into a denser region. This includes the occurrence of mergers, enhancement of star formation activity, excursion to the dusty starburst phase, and eventual quenching to a passive phase.Comment: 19 pages, 15 figures. Accepted for publication in ApJ. Error bars in Table 2 correcte

    Gain-of-function IKBKB mutation causes human combined immune deficiency

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    Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. IKBKB encodes IKK2, which activates NF-κB signaling. IKK2V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2V203 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in Ikbkb using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes arising from de novo germline mutations and yield insight into pathogenesis

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

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    「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

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

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    「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

    Effect of information provision by familial nudging on attitudes toward offshore wind power.

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    Offshore wind power (OWP) is a promising way to achieve decarbonization and tackle global climate change, but acceptance by residents is an important issue for site location. Information provision could be a more cost-effective intervention than debates or subsidies, assuming that scientifically correct information alone is insufficient and information design to boost the message effects considering realistic human responses is necessary. Thus, we designed nudging messages to increase acceptance of OWP, using a message framework to moderate risk-averse attitudes by reminding readers of familial support based on insights from kin selection theory from evolutionary psychology. A randomized controlled trial based on an internet survey of more than 4000 responses from the general public was performed to investigate the message effects. The messages significantly moderated the risk-averse attitudes toward OWP by 0.228 on average on a five-point Likert scale, which meant that about 5 people out of 100 changed their attitudes to be safer by 1 point. This suggests that disseminating flyers using nudging messages might be an effective way to increase acceptance. We also extracted responses from those who mentioned fisheries in an open-ended question as an alternative to actual fishers. Responses from this segment were more complex and the message effects were limited compared with those who did not mention fisheries; although the attitudes toward OWP before receiving the messages were safer, reading descriptions for potential risks on fisheries may have unexpectedly led them to focus on the risks of which they were unaware at first. Because information provision based on nudging is effective but just one of a wide variety of political interventions available, practitioners should consider a combination of multiple options instead of using only nudging messages
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