title: JMJD2A attenuation affects cell cycle and tumourigenic inflammatory gene regulation in lipopolysaccharide stimulated neuroectodermal stem cells.
abstract: JMJD2A is a lysine trimethyl-specific histone demethylase that is highly expressed in a variety of tumours. The role of JMJD2A in tumour progression remains unclear. The objectives of this study were to identify JMJD2A-regulated genes and understand the function of JMJD2A in p53-null neuroectodermal stem cells (p53(-/-) NE-4Cs). We determined the effect of LPS as a model of inflammation in p53(-/-) NE-4Cs and investigated whether the epigenetic modifier JMJD2A alter the expression of tumourigenic inflammatory genes. Global gene expression was measured in JMJD2A knockdown (kd) p53(-/-) NE-4Cs and in LPS-stimulated JMJD2A-kd p53(-/-) NE-4C cells. JMJD2A attenuation significantly down-regulated genes were Cdca2, Ccnd2, Ccnd1, Crebbp, IL6rα, and Stat3 related with cell cycle, proliferation, and inflammatory-disease responses. Importantly, some tumour-suppressor genes including Dapk3, Timp2 and TFPI were significantly up-regulated but were not affected by silencing of the JMJD2B. Furthermore, we confirmed the attenuation of JMJD2A also down-regulated Cdca2, Ccnd2, Crebbp, and Rest in primary NSCs isolated from the forebrains of E15 embryos of C57/BL6J mice with effective p53 inhibitor pifithrin-α (PFT-α). Transcription factor (TF) motif analysis revealed known binding patterns for CDC5, MYC, and CREB, as well as three novel motifs in JMJD2A-regulated genes. IPA established molecular networks. The molecular network signatures and functional gene-expression profiling data from this study warrants further investigation as an effective therapeutic target, and studies to elucidate the molecular mechanism of JMJD2A-kd-dependent effects in neuroectodermal stem cells should be performed.
authors.affiliation: Department of Bionanotechnology, Hanyang University, Seoul 133-791, Republic of Korea. Electronic address: amitabhdas.kn@gmail.com.
authors.forename: Amitabh
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: jincchai@gmail.com.
authors.forename: Jin Choul
authors.initials: JC
authors.lastname: Chai
authors.affiliation: Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: khjung2@gmail.com.
authors.forename: Kyoung Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Clinical Research Centre, Inha University School of Medicine, Incheon 400-711, Republic of Korea. Electronic address: nando.hu@gmail.com.
authors.forename: Nando Dulal
authors.initials: ND
authors.lastname: Das
authors.affiliation: Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: gujiju11@gmail.com.
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Kang
authors.affiliation: Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: yslee@hanyang.ac.kr.
authors.forename: Young Seek
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: hseo@hanyang.ac.kr.
authors.forename: Hyemyung
authors.initials: H
authors.lastname: Seo
authors.affiliation: Department of Bionanotechnology, Hanyang University, Seoul 133-791, Republic of Korea; Department of Molecular & Life Science, Hanyang University, 1271 Sa 3-dong, Ansan 426-791, Gyeonggi-do, Republic of Korea. Electronic address: ygchai@hanyang.ac.kr.
authors.forename: Young Gyu
authors.initials: YG
authors.lastname: Chai
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D016147:Genes, Tumor Suppressor; D056466:Histone Demethylases / Q000235:genetics*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054258:Neural Plate / Q000187:drug effects / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D008070:Lipopolysaccharides; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases; C560307:JMJD2A protein, mouse
keywords: Cell cycle; Inflammation; JMJD2A; Neuroectodermal stem cell; p53