Roleofrheumatoidarthritis-relatedproteinPAD4inhematopoiesis

类风湿性关节炎相关蛋白PAD4在造血中的作用

• 批准号: 23791107
• 负责人: NAKASHIMA Katsuhiko
• 金额: $ 2.75万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791107/
• 关键词: シトルリン化; エピジェネティクス; 造血; PADI4; 造血幹細胞

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.

肽基精氨酸脱亚胺酶4(PAD4)通过催化组蛋白H3精氨酸残基转化为瓜氨酸残基，作为转录共调节因子发挥作用。尽管PAD4在骨髓细胞中的高水平表达表明它参与了造血，但其确切的作用尚不清楚。PAD4在小鼠骨髓Lineage-Sca1+c-kit(Lsk-Sca1+c-kit)细胞中高表达，与其他前体细胞相比，PAD4通过催化组蛋白H3在其启动子上的瓜氨酸化来调控c-myc的表达。此外，在c-myc基因的上游区域，PAD4与淋巴增强因子1和组蛋白脱乙酰酶1相关。支持这些发现的是，与野生型小鼠相比，PAD4缺陷小鼠的LSK细胞，特别是多能祖细胞(MPP)，以细胞自主的方式显示出更多的增殖。综上所述，我们的结果有力地表明，PAD4通过控制c-myc的表达来调节骨髓中MPPs的增殖。