title: PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression.
abstract: Peptidylarginine deiminase 4 (PAD4) functions as a transcriptional coregulator by catalyzing the conversion of histone H3 arginine residues to citrulline residues. Although the high level of PAD4 expression in bone marrow cells suggests its involvement in haematopoiesis, its precise contribution remains unclear. Here we show that PAD4, which is highly expressed in lineage(-) Sca-1(+) c-Kit(+) (LSK) cells of mouse bone marrow compared with other progenitor cells, controls c-myc expression by catalyzing the citrullination of histone H3 on its promoter. Furthermore, PAD4 is associated with lymphoid enhancer-binding factor 1 and histone deacetylase 1 at the upstream region of the c-myc gene. Supporting these findings, LSK cells, especially multipotent progenitors, in PAD4-deficient mice show increased proliferation in a cell-autonomous fashion compared with those in wild-type mice. Together, our results strongly suggest that PAD4 regulates the proliferation of multipotent progenitors in the bone marrow by controlling c-myc expression.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Japan. nakashima@m.u-tokyo.ac.jp
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.forename: Akari
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nariai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Urano
authors.forename: Manabu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D002452:Cell Count; D002467:Cell Nucleus / Q000201:enzymology; D049109:Cell Proliferation; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000201:enzymology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D000080002:Protein-Arginine Deiminase Type 4; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D016271:Proto-Oncogene Proteins c-myc; D006867:Hydrolases; D006655:Histone Deacetylases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse