Ochiai Kyoko, Yamaoka Mari, Swaminathan Amrutha, Shima Hiroki, Hiura Hitoshi, Matsumoto Mitsuyo, Kurotaki Daisuke, Nakabayashi Jun, Funayama Ryo, Nakayama Keiko, Arima Takahiro, Ikawa Tomokatsu, Tamura Tomohiko, Sciammas Roger, Bouvet Philippe, Kundu Tapas K, Igarashi Kazuhiko
Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan.
Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai 980-8575, Japan.
Cell Rep. 2020 Dec 22;33(12):108517. doi: 10.1016/j.celrep.2020.108517.
The chromatin protein positive coactivator 4 (PC4) has multiple functions, including chromatin compaction. However, its role in immune cells is largely unknown. We show that PC4 orchestrates chromatin structure and gene expression in mature B cells. B-cell-specific PC4-deficient mice show impaired production of antibody upon antigen stimulation. The PC4 complex purified from B cells contains the transcription factors (TFs) IKAROS and IRF4. IKAROS protein is reduced in PC4-deficient mature B cells, resulting in de-repression of their target genes in part by diminished interactions with gene-silencing components. Upon activation, the amount of IRF4 protein is not increased in PC4-deficient B cells, resulting in reduction of plasma cells. Importantly, IRF4 reciprocally induces PC4 expression via a super-enhancer. PC4 knockdown in human B cell lymphoma and myeloma cells reduces IKAROS protein as an anticancer drug, lenalidomide. Our findings establish PC4 as a chromatin regulator of B cells and a possible therapeutic target adjoining IKAROS in B cell malignancies.
染色质蛋白正向共激活因子4（PC4）具有多种功能，包括染色质压缩。然而，其在免疫细胞中的作用在很大程度上尚不清楚。我们发现，PC4在成熟B细胞中协调染色质结构和基因表达。B细胞特异性PC4缺陷小鼠在抗原刺激后抗体产生受损。从B细胞中纯化的PC4复合物包含转录因子IKAROS和IRF4。在PC4缺陷的成熟B细胞中，IKAROS蛋白减少，部分原因是与基因沉默成分的相互作用减少，导致其靶基因去抑制。激活后，PC4缺陷的B细胞中IRF4蛋白的量没有增加，导致浆细胞减少。重要的是，IRF4通过超级增强子反向诱导PC4表达。在人B细胞淋巴瘤和骨髓瘤细胞中敲低PC4会使IKAROS蛋白减少，其作用类似于抗癌药物来那度胺。我们的研究结果表明，PC4是B细胞的染色质调节因子，也是B细胞恶性肿瘤中与IKAROS相邻的一个可能的治疗靶点。
