Yuuki Imai

Ehime University, Matuyama, Ehime, Japan

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Publications (58)326.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Bone mass is regulated by various molecules including endogenous factors as well as exogenous factors, such as nutrients and pollutants. Aryl hydrocarbon receptor (AhR) is known as a dioxin receptor and is responsible for various pathological and physiological processes. However, the role of AhR in bone homeostasis remains elusive because the cell type specific direct function of AhR has never been explored in vivo. Here, we show the cell type specific function of AhR in vivo in bone homeostasis. Systemic AhR knockout (AhRKO) mice exhibit increased bone mass with decreased resorption and decreased formation. Meanwhile, osteoclast specific AhRKO (AhR(ΔOc/ΔOc)) mice have increased bone mass with reduced bone resorption, although the mice lacking AhR in osteoblasts have a normal bone phenotype. Even under pathological conditions, AhR(ΔOc/ΔOc) mice are resistant to sex hormone deficiency-induced bone loss resulting from increased bone resorption. Furthermore, 3-methylcholanthrene, an AhR agonist, induces low bone mass with increased bone resorption in control mice, but not in AhR(ΔOc/ΔOc) mice. Taken together, cell type specific in vivo evidence for AhR functions indicates that osteoclastic AhR plays a significant role in maintenance of bone homeostasis, suggesting that inhibition of AhR in osteoclasts can be beneficial in the treatment of osteoporosis.
    Biochemical and Biophysical Research Communications 06/2014; · 2.41 Impact Factor
  • Kazuki Inoue, Yuuki Imai
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    ABSTRACT: Clarification of the mechanisms underlying osteoclast differentiation enables us to understand the physiology of bone metabolism as well as the pathophysiology of bone diseases such as osteoporosis. Recently, it has been reported that epigenetics can determine cell fate and regulate cell type-specific gene expression. However, little is known about epigenetics during osteoclastogenesis. To reveal a part of epigenetics, especially focused on chromatin dynamics, during early osteoclastogenesis and to identify novel transcription factors involved in osteoclastogenesis, we performed a genome-wide analysis of open chromatin during Receptor Activator of Nuclear factor-κB Ligand (RANKL)-induced osteoclastogenesis using DNase I hypersensitive sites sequencing (DNase-seq). DNase-seq was performed using the extracted nuclei from RAW264 cells treated with or without RANKL for 24 hours, followed by several bioinformatic analyses. DNase I hypersensitive sites (DHSs) were dynamically changed during RANKL-induced osteoclastogenesis and they accumulated in promoter regions. The distributions of DHSs among cis-regulatory DNA regions were identical regardless of RANKL stimulation. Motif discovery analysis successfully identified well-known osteoclastogenic transcription factors including Jun, CREB1, FOS, ATF2 and ATF4, but also novel transcription factors for osteoclastogenesis such as Zscan10, Atf1, Nrf1 and Srebf2. siRNA knockdown of these identified novel transcription factors impaired osteoclastogenesis. Taken together, DNase-seq is a useful tool for comprehension of epigenetics, especially chromatin dynamics during osteoclastogenesis and for identification of novel transcription factors involved in osteoclastogenesis. This study may reveal underlying mechanisms that determine cell type-specific differentiation of bone cells and may lead to investigate novel therapeutic targets for osteoporosis. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2014; · 6.04 Impact Factor
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    ABSTRACT: Estrogens are well known steroid hormones necessary to maintain bone health. In addition, mechanical loading, in which estrogen signaling may intersect with the Wnt/β-catenin pathway, is essential for bone maintenance. As osteocytes are known as the major mechanosensory cells embedded in mineralized bone matrix, osteocyte ERα deletion mice (ERα(ΔOcy/ΔOcy)) were generated by mating ERα floxed mice with Dmp1-Cre mice to determine the role of ERα in osteocytes. Trabecular bone mineral density of female, but not male ERα(ΔOcy/ΔOcy) mice was significantly decreased. Bone formation parameters in ERα(ΔOcy/ΔOcy) were significantly decreased while osteoclast parameters were unchanged. This suggests that ERα in osteocytes exerts osteoprotective function by positively controlling bone formation. To identify potential targets of ERα, gene array analysis of Dmp1-GFP osteocytes sorted by FACS from ERα(ΔOcy/ΔOcy) and control mice was performed. Gene expression microarray followed by gene ontology analyses revealed that osteocytes from ERα(ΔOcy/ΔOcy) highly expressed genes categorized in 'Secreted' when compared to control osteocytes. Among them, expression of Mdk and Sostdc1, both of which are Wnt inhibitors, was significantly increased without alteration of expression of the mature osteocyte marker Sost or β-catenin. Moreover, hindlimb suspension experiments showed that trabecular bone loss due to unloading was greater in ERα(ΔOcy/ΔOcy) mice with no loss of cortical bone. These data suggest that ERα in osteocytes has osteoprotective functions in trabecular bone formation through regulating expression of Wnt antagonists, but conversely plays a negative role in cortical bone loss due to unloading.
    Bone 12/2013; · 3.82 Impact Factor
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    Yosuke Okuno, Kazuki Inoue, Yuuki Imai
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    ABSTRACT: Recently, it has been progressively recognized that gene expression is regulated by histone methylation status, which is dynamically modulated by histone methyltransferases (HMTs) and histone demethylases (HDMs). In the past decade, many HMTs and HDMs were identified and their biological and biochemical functions have been characterized. As with other cells, several HMTs and HDMs are known to be indispensable for appropriate differentiation of adipocytes from mesenchymal stem cells. Phf2 is a recently identified dimethylated histone H3 lysine 9 (H3K9me2) demethylase that has a significant function in hepatocytes and macrophages in vitro; however, the in vivo significance of Phf2 remains unclear. To determine the physiological role of Phf2, we recently generated Phf2 knockout mice. Our analyses of these mice revealed that Phf2 has a positive role in adipogenesis by coactivating CEBPA, one of the master regulators of adipogenesis, through its demethylation activity toward H3K9me2. In this commentary, we discuss several remaining questions that underlie phenotypic abnormalities seen in our investigations of Phf2 knockout mice. These studies are related to novel functions of histone modifiers and may help identify new therapeutic targets for metabolic syndrome.
    Adipocyte. 10/2013; 2(4):285-8.
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    ABSTRACT: Chondrocyte differentiation is controlled by various regulators, such as Sox9 and Runx2, but the process is complex. To further understand the precise underlying molecular mechanisms of chondrocyte differentiation, we aimed to identify a novel regulatory factor of chondrocyte differentiation using gene expression profiles of micromass-cultured chondrocytes at different differentiation stages. From the results of microarray analysis, the autoimmune regulator, Aire, was identified as a novel regulator. Aire stable knockdown cells, and primary cultured chondrocytes obtained from Aire(-/-) mice, showed reduced mRNA expression levels of chondrocyte-related genes. Over-expression of Aire induced the early stages of chondrocyte differentiation by facilitating expression of BMP2. A ChIP assay revealed that Aire was recruited on an Aire binding site (T box) in the Bmp2 promoter region in the early stages of chondrocyte differentiation and histone methylation was modified. These results suggest that Aire can facilitate early chondrocyte differentiation by expression of Bmp2 through altering the histone modification status of the promoter region of Bmp2. Taken together, Aire might play a role as an active regulator of chondrocyte differentiation, which leads to new insights into the regulatory mechanisms of chondrocyte differentiation.
    Biochemical and Biophysical Research Communications 07/2013; · 2.41 Impact Factor
  • Kazuki Inoue, Erina Inoue, Yuuki Imai
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    ABSTRACT: The pathology of rheumatoid arthritis (RA) is ameliorated during pregnancy and deteriorated after delivery. Thus, female sex hormones could be involved in the pathogenesis of RA. However, the effects of estrogen and progesterone on the development and progression of RA have been unclear. In this study, we analyzed the effects of female hormones on the pathogenesis of RA by performing ovariectomy (OVX) and hormone implantation in the SKG mouse model of human RA. OVX mice showed severe arthritis and cartilage destruction with increased serum levels of TNF-α and IL-6, when compared with sham-operated mice. In contrast, estrogen-treated mice exhibited remarkable suppression of arthritis, with no bone erosion, little synovial hyperplasia and little infiltration of immune cells. Moreover, serum levels of TNF-α and IL-6 were decreased. In progesterone-treated mice, mild synovial hyperplasia and no immune cell infiltration were observed, with decreased serum levels of IL-6. These results suggest that female hormones, estrogen and progesterone, can play roles in the remission of RA.
    Biochemical and Biophysical Research Communications 04/2013; · 2.41 Impact Factor
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    ABSTRACT: During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders.
    Physiological Reviews 04/2013; 93(2):481-523. · 30.17 Impact Factor
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    ABSTRACT: The physiological and beneficial actions of vitamin D in bone health have been experimentally and clinically proven in mammals. The active form of vitamin D [1α,25(OH)(2)D(3)] binds and activates its specific nuclear receptor, the vitamin D receptor (VDR). Activated VDR prevents the release of calcium from its storage in bone to serum by stimulating intestinal calcium absorption and renal reabsorption. However, the direct action of VDR in bone tissue is poorly understood because serum Ca(2+) homeostasis is maintained through tightly regulated ion transport by the kidney, intestine, and bone. In addition, conventional genetic approaches using VDR knockout (VDR-KO, VDR(-/-)) mice could not identify VDR action in bone because of the animals' systemic defects in calcium metabolism. In this study, we report that systemic VDR heterozygous KO (VDR(+/L-)) mice generated with the Cre/loxP system as well as conventional VDR heterozygotes (VDR(+/-)) showed increased bone mass in radiological assessments. Because mineral metabolism parameters were unaltered in both types of mice, these bone phenotypes imply that skeletal VDR plays a role in bone mass regulation. To confirm this assumption, osteoblast-specific VDR-KO (VDR(ΔOb/ΔOb)) mice were generated with 2.3 kb α1(I)-collagen promoter-Cre transgenic mice. They showed a bone mass increase without any dysregulation of mineral metabolism. Although bone formation parameters were not affected in bone histomorphometry, bone resorption was obviously reduced in VDR(ΔOb/ΔOb) mice because of decreased expression of receptor activator of nuclear factor kappa-B ligand (an essential molecule in osteoclastogenesis) in VDR(ΔOb/ΔOb) osteoblasts. These findings establish that VDR in osteoblasts is a negative regulator of bone mass control.
    Endocrinology 02/2013; · 4.72 Impact Factor
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    ABSTRACT: PHF2 is a JmjC family histone demethylase that removes the methyl group from H3K9me2 and works as a coactivator for several metabolism-related transcription factors. In this study, we examined the in vivo role of PHF2 in mice. We generated Phf2 floxed mice, systemic Phf2 null mice by crossing Phf2 floxed mice with CMV-Cre transgenic mice, and tamoxifen-inducible Phf2 knockout mice by crossing Phf2 floxed mice with Cre-ERT2 transgenic mice. Systemic Phf2 null mice had partial neonatal death and growth retardation and exhibited less adipose tissue and reduced adipocyte numbers compared with control littermates. Tamoxifen-induced conditional knockout of PHF2 resulted in impaired adipogenesis in stromal vascular cells from the adipose tissue of tamoxifen-inducible Phf2 knockout mice as well as of Phf2 knocked-down 3T3-L1 cells. PHF2 interacts with CEBPA and demethylates H3K9me2 in the promoters of CEBPA-regulated adipogenic genes. These findings suggest that PHF2 histone demethylase potentiates adipogenesis through interaction with CEBPA in vivo. Taken together, PHF2 may be a novel therapeutic target in the treatment of obesity and the metabolic syndrome.
    Diabetes 12/2012; · 7.90 Impact Factor
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    Dataset: Asagiri.SOM
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    ABSTRACT: Osteoclastogenesis is a highly regulated process governed by diverse classes of regulators. Among them, nuclear factor of activated T-cells calcineurin-dependent 1 (NFATc1) is the primary osteoclastogenic transcription factor, and its expression is transcriptionally induced during early osteoclastogenesis by receptor activation of nuclear factor κB ligand (RANKL), an osteoclastogenic cytokine. Here, we report the novel enzymatic function of JMJD5, which regulates NFATc1 protein stability. Among the tested Jumonji C (JmjC) domain-containing proteins, decreased mRNA expression levels during osteoclastogenesis were found for JMJD5 in RAW264 cells stimulated by RANKL. To examine the functional role of JMJD5 in osteoclast differentiation, we established stable JMJD5 knockdown cells, and osteoclast formation was assessed. Down-regulated expression of JMJD5 led to accelerated osteoclast formation together with induction of several osteoclast-specific genes such as Ctsk and DC-STAMP, suggesting that JMJD5 is a negative regulator in osteoclast differentiation. Although JMJD5 was recently reported as a histone demethylase for histone H3K36me2, no histone demethylase activity was detected in JMJD5 in vitro or in living cells, even for other methylated histone residues. Instead, JMJD5 co-repressed transcriptional activity by destabilizing NFATc1 protein. Protein hydroxylase activity mediated by the JmjC domain in JMJD5 was required for the observed functions of JMJD5. JMJD5 induced the association of hydroxylated NFATc1 with the E3 ubiquitin ligase Von Hippel-Lindau tumor suppressor (VHL), thereby presumably facilitating proteasomal degradation of NFATc1 via ubiquitination. Taken together, the present study demonstrated that JMJD5 is a post-translational co-repressor for NFATc1 that attenuates osteoclastogenesis.
    Journal of Biological Chemistry 02/2012; 287(16):12994-3004. · 4.65 Impact Factor
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    ABSTRACT: Osteoclasts are differentiated from hematopoietic stem cells and become multinucleated giant cells through cell-fusion by a number of regulators. Among such regulators, transcription factors play pivotal roles by reorganizing gene networks. Recently, epigenetic regulators like histone modifiers and chromatin remodelers have emerged to be prerequisite for gene regulations by transcriptional factors. However, little is known about epigenetic controls during osteoclastogenesis and osteoclastic maturation. To address this issue, we tried to identify novel epigenetic regulators for fine control of NFATc1 function through biochemical approaches. Here, we summarize the new epigenetic regulation mechanism and epigenetic regulator which are required for normal osteoclastogenesis.
    Clinical calcium 01/2012; 22(5):611-7.
  • Shino Kondoh, Yuuki Imai
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    ABSTRACT: Estrogen is well-known to play essential roles for maintenance of bone mass. Although its osteoprotective actions are mediated mainly through suppressing bone resorption, several reports has suggested that ERα/estrogen signal in osteocytes has some osteoprotective effects. For example, ERαis reported to be involved in adaptive response to loading which is thought to be sensed by osteocytes. Estrogen is also thought to be a viable factor for osteocytes. In addition, our group recently found that osteocytic ERαexhibited decreased bone mass, suggesting that osteocytic ERαexerts osteoprotective function. Also, functions of osteocyte itself have been characterized recently. These findings may lead to an understanding of estrogen actions on osteocytes and to a comprehensive understanding of estrogen actions on bone.
    Clinical calcium 01/2012; 22(5):721-6.
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    ABSTRACT: Chromatin reorganization is governed by multiple post-translational modifications of chromosomal proteins and DNA. These histone modifications are reversible, dynamic events that can regulate DNA-driven cellular processes. However, the molecular mechanisms that coordinate histone modification patterns remain largely unknown. In metazoans, reversible protein modification by O-linked N-acetylglucosamine (GlcNAc) is catalysed by two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). However, the significance of GlcNAcylation in chromatin reorganization remains elusive. Here we report that histone H2B is GlcNAcylated at residue S112 by OGT in vitro and in living cells. Histone GlcNAcylation fluctuated in response to extracellular glucose through the hexosamine biosynthesis pathway (HBP). H2B S112 GlcNAcylation promotes K120 monoubiquitination, in which the GlcNAc moiety can serve as an anchor for a histone H2B ubiquitin ligase. H2B S112 GlcNAc was localized to euchromatic areas on fly polytene chromosomes. In a genome-wide analysis, H2B S112 GlcNAcylation sites were observed widely distributed over chromosomes including transcribed gene loci, with some sites co-localizing with H2B K120 monoubiquitination. These findings suggest that H2B S112 GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination, presumably for transcriptional activation.
    Nature 11/2011; 480(7378):557-60. · 38.60 Impact Factor
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    ABSTRACT: Small interfering RNA (siRNA) is useful tool for specific and efficient knockdown of disease-related genes. However, in vivo applications of siRNA are limited due to difficulty in its efficient delivery to target cells. In this study, we investigated the efficacy of a biodegradable hydrogel, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block co-polymer (PLA-DX-PEG), as a siRNA carrier. PLA-DX-PEG pellets with or without fluorescein-labeled dsRNA were implanted into mouse dosal muscle pouches. The cellular uptake of dsRNA surround the polymer was confirmed by fluorescent microscopy. The fluorescence intensity was dose-dependent of the dsRNA, and exhibited a time-dependent decrease. To investigate its biological efficiency, noggin (antagonoist to BMPs) gene-silencing with siRNA (siRNA/Noggin) was examined by the amount of suppression of BMP-2-induced noggin expression and the level of performance of BMP, indicated by ectopic bone formation. Noggin gene expression induced by BMP-2 was suppressed by addition of siRNA/Noggin to the implant, and the ectopic bone formation induced by implants with both BMP-2 and siRNA/Noggin was significantly greater than those induced by implants with BMP-2 alone. These results indicate the efficacy of local delivery of siRNAs by PLA-DX-PEG polymer, which intensified bone-inducing effects of BMP and promoted new bone formation by suppressing gene expression of Noggin.
    Biomaterials 09/2011; 32(36):9642-8. · 8.31 Impact Factor
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    ABSTRACT: Bone undergoes remodeling consisting of osteoclastic bone resorption followed by osteoblastic bone formation throughout life. Although the effects of bone morphogenetic protein (BMP) signals on osteoblasts have been studied extensively, the function of BMP signals in osteoclasts has not been fully elucidated. To delineate the function of BMP signals in osteoclasts during bone remodeling, we deleted BMP receptor type IA (Bmpr1a) in an osteoclast-specific manner using a knock-in Cre mouse line to the cathepsin K locus (Ctsk(Cre/+);Bmpr1a(flox/flox), designated as Bmpr1a(ΔOc/ΔOc)). Cre was specifically expressed in multinucleated osteoclasts in vivo. Cre-dependent deletion of the Bmpr1a gene occurred at 4 days after cultivation of bone marrow macrophages obtained from Bmpr1a(ΔOc/ΔOc) with RANKL. These results suggested that Bmpr1a was deleted after formation of osteoclasts in Bmpr1a(ΔOc/ΔOc) mice. Expression of bone-resorption markers increased, thus suggesting that BMPRIA signaling negatively regulates osteoclast differentiation. Trabeculae in tibia and femurs were thickened in 3.5-, 8-, and 12-week-old Bmpr1a(ΔOc/ΔOc) mice. Bone histomorphometry revealed increased bone volume associated with increased osteoblastic bone-formation rates (BFR) in the remodeling bone of the secondary spongiosa in Bmpr1a(ΔOc/ΔOc) tibias at 8 weeks of age. For comparison, we also induced an osteoblast-specific deletion of Bmpr1a using Col1a1-Cre. The resulting mice showed increased bone volume with marked decreases in BFR in tibias at 8 weeks of age. These results indicate that deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, thus suggesting that BMPR1A signaling in osteoclasts regulates coupling to osteoblasts by reducing bone-formation activity during bone remodeling.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2011; 26(10):2511-22. · 6.04 Impact Factor
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    ABSTRACT: Endocrine therapies for breast cancer that target the estrogen receptor (ER) are ineffective in the 25%-30% of cases that are ER negative (ER-). Androgen receptor (AR) is expressed in 60%-70% of breast tumors, independent of ER status. How androgens and AR regulate breast cancer growth remains largely unknown. We find that AR is enriched in ER- breast tumors that overexpress HER2. Through analysis of the AR cistrome and androgen-regulated gene expression in ER-/HER2+ breast cancers we find that AR mediates ligand-dependent activation of Wnt and HER2 signaling pathways through direct transcriptional induction of WNT7B and HER3. Specific targeting of AR, Wnt or HER2 signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER-/HER2+ breast cancers.
    Cancer cell 07/2011; 20(1):119-31. · 25.29 Impact Factor
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    ABSTRACT: The treatment of osteoporosis has been a critical issue in today's medical situation. Various therapeutic agents and strategies have been investigated and applied, and have proven successful in the treatment of osteoporosis. However, some concerns still remain, such as the adverse effects of such treatments. From this point of view, a search for novel therapeutic targets, such as Fas signaling, remains important.
    Expert Opinion on Therapeutic Targets 07/2011; 15(10):1143-5. · 4.90 Impact Factor
  • Yuuki Imai, Shigeaki Kato
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    ABSTRACT: Sex steroid hormones play important roles in bone metabolism through the functions of its specific nuclear receptors, estrogen receptors(ERs) and androgen receptor (AR). From the results of analyses of bone tissue specific sex steroid hormone receptors knockout mice, it has been clarified that sex steroids can directly function in bone tissue as well as indirect endocrine influences. These recent researches may promote the investigations of novel strategies to treat osteoporosis, which could be induced by deficiency of sex steroid hormones in the old population regardless of gender.
    Nippon rinsho. Japanese journal of clinical medicine 07/2011; 69(7):1198-202.
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    ABSTRACT: Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2-ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2-ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2-ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex.
    Nature Cell Biology 06/2011; 13(6):668-75. · 20.76 Impact Factor

Publication Stats

881 Citations
326.50 Total Impact Points

Institutions

  • 2013
    • Ehime University
      Matuyama, Ehime, Japan
  • 2007–2013
    • The University of Tokyo
      • Institute of Molecular and Cellular Biosciences
      Tokyo, Tokyo-to, Japan
  • 2004–2013
    • Osaka City University
      • Department of Orthopaedic Surgery
      Ōsaka, Ōsaka, Japan
  • 2010
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 2005
    • Shinshu University
      • Department of Orthopaedic Surgery
      Shonai, Nagano, Japan