KLF14 biology: its physiological roles and transcriptional regulation

• Project/Area Number: 25460409
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: NAKABAYASHI Kazuhiko 国立研究開発法人国立成育医療研究センター, 周産期病態研究部, 室長 (10415557)
• Co-Investigator(Renkei-kenkyūsha): TAKADA Shuji 国立成育医療研究センター, 研究所, 部長 (20382856) ; TOMIKAWA Junko 国立成育医療研究センター, 研究所, 研究員 (80534990) ; TAYAMA Chiharu 国立成育医療研究センター, 研究所, 研究員 (60774445)
• Research Collaborator: SUGAHARA Naoko 国立成育医療研究センター, 研究所, 研究補助員
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ゲノムインプリンティング / KLF14 / 白色脂肪組織 / Klf14 / genomic imprinting / white adipose tissue

Outline of Final Research Achievements

KLF14 has been proposed to act as a master regulator of key metabolic genes in adipose tissue. Cis-regulatory SNPs in the KLF14 locus are associated with susceptibility to multiple metabolic diseases including T2D. We aimed to elucidate physiological functions of KLF14 in the white adipose tissue (WAT), and to establish materials and methods to study molecular mechanisms underlying imprinted gene expression of Mest and Klf14 genes, which are located within a 200kb genomic interval.
We revealed that KLF14 involves in controlling obesity-induced inflammation in WAT by analyzing the phenotype of Klf14 knockout mice. We also successfully established mouse lines with a targeted deletion of the germline differentially methylated region at the Mest promoter region, which is expected to play a central role in the regulation of imprinted expression of Klf14.

Research Products

• [Journal Article] Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome (2017)
  • Author(s): Okuno Hironobu、Nakabayashi Kazuhiko、Abe Kousei、Ando Takayuki、Sanosaka Tsukasa、Kohyama Jun、Akamatsu Wado、Ohyama Manabu、Takahashi Takao、Kosaki Kenjiro、Okano Hideyuki
  • Journal Title: Congenital Anomalies Volume: 57 Issue: 4 Pages: 96-103
  • DOI: 10.1111/cga.12206
  • Peer Reviewed
• [Journal Article] Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome (2017)
  • Author(s): Kagami M, Matsubara K, Nakabayashi K, Nakamura A, Sano S, Okamura K, Hata K, Fukami M, Ogata T.
  • Journal Title: Genet. Med. Volume: 19 Pages: 476-482
  • DOI: 10.1038/gim.2016.123
  • Peer Reviewed / Open Access
• [Journal Article] Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv–TET1 catalytic domain fusions (2016)
  • Author(s): Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, Sakai A, Nakashima H, Hata K, Nakashima K, Hatada I
  • Journal Title: Nat. Biotechnol. Volume: 34 Pages: 1060-1065
  • DOI: 10.1038/nbt.3658
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Human Oocyte-Derived Methylation Differences Persist in the Placenta Revealing Widespread Transient Imprinting. (2016)
  • Author(s): Sanchez-Delgado M, Court F, Vidal E, Medrano J, Monteagudo-Sanchez A, Martin-Trujillo A, Tayama C, Iglesias-Platas I, Kondova I, Bontrop R, Poo-Llanillo ME, Marques-Bonet T, Nakabayashi K, Simon C, Monk D.
  • Journal Title: PLoS Genet. Volume: 12
  • DOI: 10.1371/journal.pgen.1006427
  • Peer Reviewed / Open Access
• [Journal Article] Gene expression profiling of white adipose tissue reveals paternal transmission of proneness to obesity. (2016)
  • Author(s): Morita S, Nakabayashi K, Kawai T, Hayashi K, Horii T, Kimura M, Kamei Y, Ogawa Y, Hata K, Hatada I.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 21693-21693
  • DOI: 10.1038/srep21693
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive. (2016)
  • Author(s): Maupetit-Méhouas S, Montibus B, Nury D, Tayama C, Wassef M, Kota SK, Fogli A, Cerqueira Campos F, Hata K, Feil R, Magueron R, Nakabayashi K, Court F, Arnaud P
  • Journal Title: Nucleic Acids Res. Volume: 44 Pages: 621-635
  • DOI: 10.1093/nar/gkv960
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Absence of maternal methylation in biparental hydatidiform moles with NLRP7 maternal-effect mutations reveals widespread placenta-specific imprinting. (2016)
  • Author(s): Uchi R, Takahashi Y, Niida A, Shimamura T, Hirata H, Sugimachi K, Sawada G, Iwaya T, Kurashige J, Shinden Y, Iguchi T, Eguchi H, Chiba K, Shiraishi Y, Nagae G, et al
  • Journal Title: PLoS Genetics Volume: 12(2)
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic, epigenomic, and transcriptomic profiling towards identifying omics features and specific biomarkers that distinguish uterine leiomyosarcoma and leiomyoma at molecular levels. (2015)
  • Author(s): Miyata T, Sonoda K, Tomikawa J, Tayama C, Maehara K, Kobayashi H, Wake N, Kato K, Hata K, Nakabayashi K
  • Journal Title: Sarcoma Volume: 2015 Pages: 1-14
  • DOI: 10.1155/2015/412068
  • Peer Reviewed / Open Access
• [Journal Article] Lists of HumanMethylation450 BeadChip probes with nucleotide-variant information obtained from the Phase 3 data of the 1000 Genomes Project. (2015)
  • Author(s): Okamura K, Kawai T, Hata K, Nakabayashi K
  • Journal Title: Genomics Data Volume: 7 Pages: 67-9
  • Peer Reviewed / Open Access
• [Journal Article] An insulator element located at the cyclin B1 interacting protein 1 gene locus is highly conserved among mammalian species. (2015)
  • Author(s): Yoshida W, Tomikawa J, Inaki M, Kimura H, Onodera M, Hata K, Nakabayashi K
  • Journal Title: PLoS One Volume: 10
  • DOI: 10.1371/journal.pone.0131204
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation analysis of human myoblasts during in vitro myogenic differentiation: de novo methylation of promoters of muscle-related genes and its involvement in transcriptional down-regulation. (2015)
  • Author(s): Miyata K, Miyata T, Nakabayashi K, Okamura K, Naito M, Kawai T, Takada S, Kato K, Miyamoto S, Hata K, Asahara H
  • Journal Title: Hum Mol Genet Volume: 24 Pages: 410-23
  • DOI: 10.1093/hmg/ddu457
  • Peer Reviewed / Open Access
• [Journal Article] Role of Maternal-Specific H3K9me3 Modification in Establishing Imprinted X-Chromosome Inactivation and Embryogenesis in Mice. (2014)
  • Author(s): Fukuda A, Tomikawa J, Miura T, Hata K, Nakabayashi K, Eggan K, Akutsu H, Umezawa A.
  • Journal Title: Nature Communicaitons Volume: 5 Pages: 5464-5464
  • DOI: 10.1038/ncomms6464
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Offspring production with sperm grown in vito from cryopreserved testis tissues (2014)
  • Author(s): Yokonishi T, Sato T, Komeya M, Katagiri K, Kubota Y, Nakabayashi K, Hata K, Inoue K, Ogonuki N, Ogura A, Ogawa T
  • Journal Title: Nature communications Volume: 5 Pages: 4320-4320
  • DOI: 10.1038/ncomms5320
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations. (2014)
  • Author(s): Maeda T, Higashimoto K, Jozaki K, Hitomi H, Nakabayashi K, Makita Y, Tonoki H, Okamoto N, Takada F, Ohashi H, Migita M, Kosaki R, Matsubara K, Ogata T, Matsuo M, Hamasaki Y, Ohtsuka Y, Nishioka K, Joh K, Mukai T, Hata K, Soejima H
  • Journal Title: Genetics in Medicine Volume: 16(12) Pages: 903-12
  • DOI: 10.1038/gim.2014.46
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Variable maternal methylation overlapping the nc886/vtRNA2-1 locus is locked between hypermethylated repeats and is frequently altered in cancer. (2014)
  • Author(s): Romanelli V, Nakabayashi K, Vizoso M, Moran S, Iglesias-Platas I, Sugahara N, Simón C, Hata K, Esteller M, Court F, Monk D.
  • Journal Title: Epigenetics Volume: 9 Pages: 783-790
  • DOI: 10.4161/epi.28323
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. (2014)
  • Author(s): Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simon C, Moore H, Harness J, Keirstead H, Vicente Sanchez-Mut J, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D
  • Journal Title: Genome Reserch. Volume: 24 (4) Pages: 554-569
  • DOI: 10.1101/gr.164913.113
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epigenetic and transcriptional features of the novel human imprinted lncRNA GPR1AS suggest it is a functional ortholog to mouse Zdbf2linc (2013)
  • Author(s): Kobayashi H, Yanagisawa E, Sakashita A, Sugawara N, Kumakura S, Ogawa H, Akutsu H, Hata K, Nakabayashi K, Kono T.
  • Journal Title: Epigenetics Volume: 8 (6) Pages: 635-45
  • DOI: 10.4161/epi.24887
  • Peer Reviewed
• [Presentation] KLF14 involves in controlling inflammation in the white adipose tissue. (2016)
  • Author(s): Tayama C, Takanashi R, Tomikawa J, Okita H, Hata K, Okamura T, Nakabayashi K.
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto
  • Int'l Joint Research
• [Presentation] 父性遺伝する食事誘導性肥満におけるインプリント遺伝子の解析と新規インプリント遺伝子の探索について． (2016)
  • Author(s): 森田純代，中林一彦，河合智子，林恵子，堀居拓郎，木村美香，亀井康富，小川佳宏，秦健一郎，畑田出穂
  • Organizer: 第10回日本エピジェネティクス研究会年会
  • Place of Presentation: 大阪
• [Presentation] 成育・周産期関連疾患解明のためのエピゲノム解析 (2016)
  • Author(s): 中林一彦
  • Organizer: 金沢大学学際科学実験センター・サイエンスセミナー
  • Place of Presentation: 金沢
  • Invited
• [Presentation] 転写因子 KLF14 の白色脂肪組織における炎症制御への関与 (2015)
  • Author(s): 中林一彦,田山千春，高梨理絵子，冨川順子，大喜多肇，秦健一郎，岡村匡史
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-15
  • Int'l Joint Research
• [Presentation] KLF14 involves in controlling inflammation in the white adipose tissue. (2015)
  • Author(s): Tayama C, Takanashi E, Tomikawa J, Okita H, Hata K, Okamura T, Nakabayashi K
  • Organizer: The 65th Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: Baltimore
  • Year and Date: 2015-10-07
  • Int'l Joint Research
• [Presentation] 次世代シーケンサーを用いた遺伝子・ゲノム診断 (2015)
  • Author(s): 中林一彦
  • Organizer: 第25回日本サイトメトリー学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-12
  • Invited
• [Presentation] 転写因子KLF14の白色脂肪組織における炎症制御への関与 (2014)
  • Author(s): 田山 千春，高梨(矢延) 理絵子，富川 順子，大喜多 肇，秦 健一郎，岡村 匡史，中林 一彦
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25
• [Presentation] ヒトインプリントーム解析から見えてきたヒト（霊長類）特異的エピゲノム進化 (2014)
  • Author(s): 中林一彦
  • Organizer: 京都大学霊長類研究所・研究会「霊長類への展開に向けた幹細胞・生殖細胞・エピゲノム研究」
  • Place of Presentation: 京都大学・霊長類研究所
  • Year and Date: 2014-08-27
  • Invited