Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4

• Published in: Cell reports (Cambridge) Vol. 33; no. 12; p. 108517
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.12.2020
• Subjects: Animals; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Cell Differentiation - physiology; Cell Line, Tumor; cell survival; chromatin; complex purification; DNA-Binding Proteins - metabolism; human B cell malignancy; Humans; IKAROS; Ikaros Transcription Factor - metabolism; Interferon Regulatory Factors - metabolism; IRF4; mature B cell; Mice; Mice, Transgenic; PC4; plasma cell differentiation; Transcription Factors - metabolism; PC4; plasma cell differentiation; human B cell malignancy; cell survival; IRF4; IKAROS; mature B cell; chromatin; complex purification
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •PC4 deficiency in B cells results in a reduced response to antigen stimulation•PC4 maintains mature B cell function by regulating gene expression with IKAROS•PC4 and IKAROS promote high IRF4 protein levels upon antigen stimulation•PC4 knockdown reduces IKAROS protein in human B cell lymphoma and myeloma cells PC4 is involved in various functions, including chromatin organization. Ochiai et al. find that PC4 maintains mature B cell function in response to antigen stimulation and plasma cell differentiation. Additionally, the authors show that PC4 could be an effective therapeutic target in human B cell lymphoma and myeloma cells.