Symmetrically dimethylated histone H3R2 promotes global transcription during minor zygotic genome activation in mouse pronuclei

受精卵の発生に重要な因子を発見 --ヒストンのアルギニンジメチル化が重要--. 京都大学プレスリリース. 2021-05-13.Paternal genome reprogramming, such as protamine–histone exchange and global DNA demethylation, is crucial for the development of fertilised embryos. Previously, our study showed that one of histone arginine methylation, asymmetrically dimethylated histone H3R17 (H3R17me2a), is necessary for epigenetic reprogramming in the mouse paternal genome. However, roles of histone arginine methylation in reprogramming after fertilisation are still poorly understood. Here, we report that H3R2me2s promotes global transcription at the 1-cell stage, referred to as minor zygotic genome activation (ZGA). The inhibition of H3R2me2s by expressing a histone H3.3 mutant H3.3R2A prevented embryonic development from the 2-cell to 4-cell stages and significantly reduced global RNA synthesis and RNA polymerase II (Pol II) activity. Consistent with this result, the expression levels of MuERV-L as minor ZGA transcripts were decreased by forced expression of H3.3R2A. Furthermore, treatment with an inhibitor and co-injection of siRNA to PRMT5 and PRMT7 also resulted in the attenuation of transcriptional activities with reduction of H3R2me2s in the pronuclei of zygotes. Interestingly, impairment of H3K4 methylation by expression of H3.3K4M resulted in a decrease of H3R2me2s in male pronuclei. Our findings suggest that H3R2me2s together with H3K4 methylation is involved in global transcription during minor ZGA in mice

一過性エノラートによる触媒的３成分タンデム反応の開発

13301甲第5274号博士(創薬科学)金沢大学博士論文要旨Abstract 以下に掲載：Green Chemistry 23(3) pp.1160-1164 2021. Royal Society of Chemistry. 共著者：Shunya Morita, Tomoyuki Yoshimura, Jun-ichi Matsu

Indication of Pd–C or Cu–C Intermediates in Bimetallic Nanoclusters During Pd/Au-PVP- or Cu/Au-PVP-Catalyzed Oxidations of endo-4-Oxatricyclo[5.2.1.02,6]-8-decene and Tetrahydro-γ-carbolines

Catalytic oxidation of tricyclic endo-norbornene-fused tetrahydrofuran with the bimetallic nanocluster Cu/Au-PVP in the presence of H2O2 or t-BuOOH as the oxidant leads to C–H bond oxidation adjacent to the ether function to give 4-oxa-tricyclo[5.2.1.0]-8,9-exo-epoxydecane, however, oxidation with Pd/Au-PVP takes place at the C=C double bond to give the same epoxide and the oxidative three-bond forming dimeric product, dodecahydro-1,4:6,9-dimethanodibenzofurano[2,3-b:7,8-b′]bisoxolane. Formation of the latter product suggests the involvement of a reactive Pd–C intermediate. Similarly, oxidative C–C bond-forming reactions are observed in cycloaddition reactions of N2-Boc-1,2,3,4-tetrahydro-γ-carbolines and 2,3-dihydroxybenzoic acid with Cu/Au-PVP (2–5 mol%) and H2O2 at 25 °C, providing two-bond-forming [4+2] cycloadducts. Under similar reaction conditions, Pd/Au-PVP did not produce the corresponding cycloadduct, indicating a need for complexation between Cu and the carboxylic acid group of 2,3-dihydroxybenzoic acid and the allylic amine function of the γ-carbolines during the cyclization reaction. The reported intermolecular coupling reactions using Pd/Au-PVP or Cu/Au-PVP nanocluster catalysts under oxidative conditions at 25 °C are unprecedented

A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia

We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5 +/- 18.7 vs. 183.3 +/- 22.9 mm(3), p < 0.01). In permanent focal ischemia, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced infarct volume (242.1 +/- 32.3, 201.3 +/- 15.1, and 171.3 +/- 15.2 mm(3), respectively), and improved neurological deficits. Reduction of infarct volume is demonstrable, provided that TM2002 was administered within 1.5 h after the occlusion. To unravel TM2002's mechanism of action, we examined its in vitro effect on endoplasmic reticulum (ER) stress, using aortic smooth muscle cells isolated from ORP 150(+/-) mice and F9 Herp null mutated cells. Cell death induced by ER stress (tunicamycin or hypoxia) was dose-dependently prevented by TM2002. In vivo immunohistochemical study demonstrated a significant reduction of ORP- and TUNEL-positive apoptotic cells, especially in the penumbra. Inhibition of advanced glycation and oxidative stress was confirmed by a significantly reduced number of cells positive for advanced glycation end products and heme oxygenase-1. TM2002 reduced the levels of protein carbonyl formation in ischemic caudate. The efficacy of TM2002 is equivalent to that of a known neuroprotective agent, NXY-059. In conclusion, TM2002 significantly ameliorates ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood pressure lowering. (c) 2007 Published by Elsevier B.V

Synthesis and Characterization of Bimetallic Nanoclusters Stabilized by Chiral and Achiral Polyvinylpyrrolidinones. Catalytic C(sp3)–H Oxidation

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Organic Chemistry, copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.joc.2c00449.Second-generation chiral-substituted poly-N-vinylpyrrolidinones (CSPVPs) (−)-1R and (+)-1S were synthesized by free-radical polymerization of (3aR,6aR)- and (3aS,6aS)-5-ethenyl-tetrahydro-2,2-dimethyl-4H-1,3-dioxolo[4,5-c]pyrrol-4-one, respectively, using thermal and photochemical reactions. They were produced from respective d-isoascorbic acid and d-ribose. In addition, chiral polymer (−)-2 was also synthesized from the polymerization of (S)-3-(methoxymethoxy)-1-vinylpyrrolidin-2-one. Molecular weights of these chiral polymers were measured using HRMS, and the polymer chain tacticity was studied using 13C NMR spectroscopy. Chiral polymers (−)-1R, (+)-1S, and (−)-2 along with poly-N-vinylpyrrolidinone (PVP, MW 40K) were separately used in the stabilization of Cu/Au or Pd/Au nanoclusters. CD spectra of the bimetallic nanoclusters stabilized by (−)-1R and (+)-1S showed close to mirror-imaged CD absorption bands at wavelengths 200–300 nm, revealing that bimetallic nanoclusters’ chiroptical responses are derived from chiral polymer-encapsulated nanomaterials. Chemo-, regio-, and stereo-selectivity was found in the catalytic C–H group oxidation reactions of complex bioactive natural products, such as ambroxide, menthofuran, boldine, estrone, dehydroabietylamine, 9-allogibberic acid, and sclareolide, and substituted adamantane molecules, when catalyst Cu/Au (3:1) or Pd/Au (3:1) stabilized by CSPVPs or PVP and oxidant H2O2 or t-BuOOH were applied. Oxidation of (+)-boldine N-oxide 23 using NMO as an oxidant yielded 4,5-dehydroboldine 27, and oxidation of (−)-9-allogibberic acid yielded C6,15 lactone 47 and C6-ketone 48