PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c-myc expression

Katsuhiko Nakashima (), Satoko Arai, Akari Suzuki, Yuko Nariai, Takeshi Urano, Manabu Nakayama, Osamu Ohara, Ken-ichi Yamamura, Kazuhiko Yamamoto and Toru Miyazaki
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Katsuhiko Nakashima: 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
Satoko Arai: 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
Akari Suzuki: Graduate School of Medicine, The University of Tokyo
Yuko Nariai: Shimane University School of Medicine
Takeshi Urano: Shimane University School of Medicine
Manabu Nakayama: Kazusa DNA Research Institute
Osamu Ohara: Kazusa DNA Research Institute
Ken-ichi Yamamura: Center for Animal Resources and Development, Kumamoto University
Kazuhiko Yamamoto: Graduate School of Medicine, The University of Tokyo
Toru Miyazaki: 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

Nature Communications, 2013, vol. 4, issue 1, 1-8

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2862

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