Roleofrheumatoidarthritis-relatedproteinPAD4inhematopoiesis

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Peptidylarginine deiminase 4 (PAD4) functions as a transcriptional co-regulator bycatalyzing the conversion of histone H3 arginine residues to citrulline residues. Although the high level of PAD4 expression in bone marrow cells suggests itsinvolvement in hematopoiesis, its precise contribution remains unclear. Here, weshow that PAD4, which is highly expressed in lineage- Sca1+ c-kit (LSK) cells of mousebone marrow compared with other progenitor cells, controls c-myc expression bycatalyzing the citrullination of histone H3 on its promoter. Furthermore, PAD4 isassociated with lymphoid enhancer-binding factor 1 and histone deacetylase 1 at theupstream region of the c-myc gene. Supporting these findings, LSK cells, especiallymulti-potent progenitors (MPPs), in PAD4-deficient mice show increased proliferationin a cell-autonomous fashion compared with those in wild-type mice. Together, ourresults strongly suggest that PAD4 regulates the proliferation of MPPs in the bonemarrow by controlling c-myc expression.