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Affiliation |
Organization for Promotion of Research and Industry-Academic Regional Collaboration Institute for Tenure Track Promotion |
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Title |
Associate Professor |
HIGASHIJIMA Yoshiki
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Research Areas 【 display / non-display 】
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Life Science / Molecular biology
Papers 【 display / non-display 】
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Acetylation of histone H2B marks active enhancers and predicts CBP/p300 target genes. International journal
Takeo Narita, Yoshiki Higashijima, Sinan Kilic, Tim Liebner, Jonas Walter, Chunaram Choudhary
Nature genetics 55 ( 4 ) 679 - 692 2023.4
Language：English Publishing type：Research paper (scientific journal)
Chromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength and identifying their target genes is challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a signature of active enhancers. H2BNTac prominently marks candidate active enhancers and a subset of promoters and discriminates them from ubiquitously active promoters. Two mechanisms underlie the distinct H2BNTac specificity: (1) unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300; (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms current state-of-the-art models in predicting CBP/p300 target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling CBP/p300-dependent gene regulation.
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Lysine demethylase 2B regulates angiogenesis via Jumonji C dependent suppression of angiogenic transcription factors. International journal
Yuji Sasaki, Yoshiki Higashijima, Jun-Ichi Suehiro, Takehito Sugasawa, Eri Oguri-Nakamura, Shigetomo Fukuhara, Nao Nagai, Yosuke Hirakawa, Youichiro Wada, Masaomi Nangaku, Yasuharu Kanki
Biochemical and biophysical research communications 605 16 - 23 2022.3
Language：English Publishing type：Research paper (scientific journal)
Vascular endothelial growth factor (VEGF) signaling plays a central role in vascular development and maintenance of vascular homeostasis. In endothelial cells (ECs), VEGF activates the gene expression of angiogenic transcription factors (TFs), followed by induction of downstream angiogenic responsive genes. Recent findings support that histone modification dynamics contribute to the transcriptional control of genes that are important for EC functions. Lysine demethylase 2B (KDM2B) demethylates histone H3K4me3 and H3K36me2/3 and mediates the monoubiquitination of histone H2AK119. KDM2B functions as a transcriptional repressor in somatic cell reprogramming and tumor development. However, the role of KDM2B in VEGF signaling remains to be elucidated. Here, we show that KDM2B knockdown enhances VEGF-induced angiogenesis in cultured human ECs via increased migration and proliferation. In contrast, ectopic expression of KDM2B inhibits angiogenesis. The function of KDM2B may depend on its catalytic Jumonji C domain. Genome-wide analysis further reveals that KDM2B selectively controls the transcription of VEGF-induced angiogenic TFs that are associated with increased H3K4me3/H3K36me3 and decreased H2AK119ub. These findings suggest an essential role of KDM2B in VEGF signaling in ECs. As dysregulation of VEGF signaling in ECs is involved in various diseases, including cancer, KDM2B may be a potential therapeutic target in VEGF-mediated vasculopathic diseases.
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Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis
Yasuharu Kanki, Masashi Muramatsu, Yuri Miyamura, Kenta Kikuchi, Yoshiki Higashijima, Ryo Nakaki, Jun-ichi Suehiro, Yuji Sasaki, Yoshiaki Kubota, Haruhiko Koseki, Hiroshi Morioka, Tatsuhiko Kodama, Mitsuyoshi Nakao, Daisuke Kurotaki, Hiroyuki Aburatani, Takashi Minami
Cell Reports 38 ( 6 ) 110332 - 110332 2022.2
Publishing type：Research paper (scientific journal) Publisher：Elsevier BV
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Inhibition of cardiac PERK signaling promotes peripartum cardiac dysfunction. International journal
Takashi Shimizu, Akashi Taguchi, Yoshiki Higashijima, Yasuharu Kanki, Ryo Nakaki, Yoshihiro Urade, Youichiro Wada
Scientific reports 11 ( 1 ) 18687 - 18687 2021.9
Language：English Publishing type：Research paper (scientific journal)
Peripartum cardiomyopathy (PPCM) is a life-threatening heart failure occurring in the peripartum period. Although mal-angiogenesis, induced by the 16-kDa N-terminal prolactin fragment (16 K PRL), is involved in the pathogenesis, the effect of full-length prolactin (23 K PRL) is poorly understood. We transfected neonate rat cardiomyocytes with plasmids containing 23 K PRL or 16 K PRL in vitro and found that 23 K PRL, but not 16 K PRL, upregulated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling, and hypoxia promoted this effect. During the perinatal period, cardiomyocyte-specific PERK homogenous knockout (CM-KO) mice showed PPCM phenotypes after consecutive deliveries. Downregulation of PERK or JAK/STAT signaling and upregulation of apoptosis were observed in CM-KO mouse hearts. Moreover, in bromocriptine-treated CM-KO mice, cardiac function did not improve and cardiomyocyte apoptosis was not suppressed during the peripartum period. These results demonstrate that interaction between 23 K PRL and PERK signaling is cardioprotective during the peripartum term.
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Potential roles of super enhancers in inflammatory gene transcription. International journal
Yoshiki Higashijima, Yasuharu Kanki
The FEBS journal 2021.6
Language：English Publishing type：Research paper (scientific journal)
Acute and chronic inflammation is a basic pathological event that contributes to atherosclerosis, cancer, infectious diseases, and immune disorders. Inflammation is an adaptive process to both external and internal stimuli experienced by the human body. Although the mechanism of gene transcription is highly complicated and orchestrated in a timely and spatial manner, recent developments in next-generation sequencing, genome-editing, cryo-electron microscopy, and single cell-based technologies could provide us with insights into the roles of super enhancers (SEs). Initially, SEs were implicated in determining cell fate; subsequent studies have clarified that SEs are associated with various pathological conditions, including cancer and inflammatory diseases. Recent technological advances have unveiled the molecular mechanisms of SEs, which involve epigenetic histone modifications, chromatin three-dimensional structures, and phase-separated condensates. In this review, we discuss the relationship between inflammation and SEs and the therapeutic potential of SEs for inflammatory diseases.
DOI： 10.1111/febs.16089
Presentations 【 display / non-display 】
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遺伝子転写とヒストンアセチル化 Invited
東島佳毅
第13回トランスポーター研究会九州部会 2023.8.5
Event date： 2023.8.5
Language：Japanese Presentation type：Oral presentation (invited, special)
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A unique H2B acetylation signature marks active enhancers and predicts their target genes
Yoshiki Higashijima
Precision Medicine Forum 2022, Epigenetics and Epigenomics in Health and Disease 2022.11.18
Event date： 2022.11.17 - 2022.11.19
Language：English Presentation type：Poster presentation
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Revising the function of transcriptional enhancer Invited
2022.3.4
Event date： 2022.3.4 - 2022.3.5
Language：English Presentation type：Oral presentation (invited, special)
Grant-in-Aid for Scientific Research 【 display / non-display 】
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Identification of novel miRNAs contributing the onset of atherosclerosis
Grant number：17K15991 2017.04 - 2020.03
Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B) Grant-in-Aid for Young Scientists (B)
Higashijima Yoshiki
Authorship：Principal investigator
Cardiovascular disease is one of the leading causes of death in developed countries. Atherosclerosis is responsible for cardiovascular disease and it is expected to develop novel diagnostic markers or therapeutic targets for atherosclerosis. In this study, we examined transcriptional changes of human endothelial cells during inflammatory responses by using microarray and next generation sequences. As a result, we identified a novel miRNA, miR-3679-5p that contributes to the onset of atherosclerosis (i.e. induction of cell adhesion molecules). Exosome is a small vesicle that is secreted into body fluid including blood and urine, and its potential uses as diagnostic marker or drug vehicle are also expected. Now, we are analyzing exosomal miR-3679-5p from human patients serum to examine whether exosomal miR-3679-5p could be useful for diagnostic marker as well as therapeutic target.
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ｍｉＲＮＡがヒストン修飾の変化を介して動脈硬化を進展させる機序の解明
Grant number：17J07088 2017.04 - 2020.03
日本学術振興会 科学研究費助成事業 特別研究員奨励費 特別研究員奨励費
東島 佳毅
Authorship：Principal investigator
申請者は採用期間初年度（平成29年度）に動脈硬化に寄与する新規miRNAを複数同定した。翌平成30年度は同定した新規miRNAの標的遺伝子探索を行い、動脈硬化に寄与する新規miRNAが共通してヒストン修飾酵素を標的とすることを見出した。最終年度となる令和元年度は、これまでの研究で見出したヒストン修飾酵素の血管内皮細胞における機能について、生化学および薬理学的手法を用いてより詳細に解析を行った。その結果、正常時の血管内皮細胞ではヒストン修飾酵素が協調的に働き炎症性遺伝子の発現を抑制していること、またこれらヒストン修飾酵素による遺伝子発現抑制機構の破綻が炎症性遺伝子の転写活性化および動脈硬化初期病巣形成に関与する可能性が示唆された。現在、ヘテロ二本鎖核酸と呼ばれる新規人工機能核酸を用いて、血管内皮細胞特異的にヒストン修飾酵素の発現を制御する手法の開発に取り組んでおり、血管内細胞特異的に発現するCD31やVE-Cadherinに対する抗体をヘテロ二本鎖核酸に結合させることで、血管内細胞特異的なヘテロ二本鎖核酸の輸送を試みている。in vitroおよび野生型マウスにおいて血管内皮細胞特異的なヘテロ二本鎖核酸の輸送を確認した後、最終的には動脈硬化モデルであるApoE欠損マウスにヘテロ二本鎖核酸を投与し血管内細胞特異的にヒストン修飾酵素の発現を制御することで、実際の生体においてヒストン修飾酵素が動脈硬化の発症および進展に関与するかどうかについて検討する予定である。