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

• DOI: 10.1038/ncomms2862
• Publication Date: 2013-05-14T07:44:41Z
• Authors: Katsuhiko Nakashima; Satoko Arai; Akari Suzuki; Yuko Nariai; Takeshi Urano; Manabu Nakayama; Osamu Ohara; Ken-ichi Yamamura; Kazuhiko Yamamoto; Toru Miyazaki
• Keywords: Cell Nucleus; 0301 basic medicine; Hydrolases; Lymphoid Enhancer-Binding Factor 1; Multipotent Stem Cells; Cell Count; Hematopoietic Stem Cells; Article; Histone Deacetylases; Mice, Inbred C57BL; Proto-Oncogene Proteins c-myc; Mice; Protein Transport; 03 medical and health sciences; HEK293 Cells; Protein-Arginine Deiminase Type 4; Animals; Humans; Promoter Regions, Genetic; Cell Proliferation

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.