title: The histone demethylase Fbxl11/Kdm2a plays an essential role in embryonic development by repressing cell-cycle regulators.
abstract: Methylation and de-methylation of histone lysine residues play pivotal roles in mammalian early development; these modifications influence chromatin architecture and regulate gene transcription. Fbxl11 (F-box and leucine-rich repeat 11)/Kdm2a is a histone demethylase that selectively removes mono- and di-methylation from histone H3K36. Previously, two other histone H3K36 demethylases (Jmjd5 or Fbxl10) were analyzed based on the phenotypes of the corresponding knockout (KO) mice; the results of those studies implicated H3K36 demethylases in cell proliferation, apoptosis, and senescence (Fukuda et al., 2011; Ishimura et al., 2012). To elucidate the physiological role of Fbxl11, we generated and examined Fbxl11 KO mice. Fbxl11 was expressed throughout the body during embryogenesis, and the Fbxl11 KO mice exhibited embryonic lethality at E10.5-12.5, accompanied with severe growth defects leading to reduced body size. Furthermore, knockout of Fbxl11 decreased cell proliferation and increased apoptosis. The lack of Fbxl11 resulted in downregulation of the Polycomb group protein (PcG) Ezh2, PcG mediated H2A ubiquitination and upregulation of the cyclin-dependent kinase inhibitor p21Cip1. Taken together, our findings suggest that Fbxl11 plays an essential role in embryonic development and homeostasis by regulating cell proliferation and survival.
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; The Tokunaga Laboratory, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasamamachi, Yufu-shi, Oita 879-5593, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kawakami
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; The Tokunaga Laboratory, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasamamachi, Yufu-shi, Oita 879-5593, Japan. Electronic address: aktoku@oita-u.ac.jp.
authors.forename: Akinori
authors.initials: A
authors.lastname: Tokunaga
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000166:cytology / Q000201:enzymology; D047108:Embryonic Development; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006657:Histones / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; D063146:Polycomb-Group Proteins; C547579:FBXL11 protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases
keywords: Embryogenesis; Fbxl11; Histone demethylase; Kdm2a; p21