@article{072e1fc2e6d9461da53c6b3197586aed,
title = "Chromatin Protein PC4 Orchestrates B Cell Differentiation by Collaborating with IKAROS and IRF4",
abstract = "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.",
keywords = "cell survival, chromatin, complex purification, human B cell malignancy, IKAROS, IRF4, mature B cell, PC4, plasma cell differentiation",
author = "Kyoko Ochiai and Mari Yamaoka and Amrutha Swaminathan and Hiroki Shima and Hitoshi Hiura and Mitsuyo Matsumoto and Daisuke Kurotaki and Jun Nakabayashi and Ryo Funayama and Keiko Nakayama and Takahiro Arima and Tomokatsu Ikawa and Tomohiko Tamura and Roger Sciammas and Philippe Bouvet and Kundu, {Tapas K.} and Kazuhiko Igarashi",
note = "Funding Information: The authors thank S. Tashiro (Hiroshima University), T. Ikura (Kyoto University), A. Muto, and S. Kaypee (Tohoku University) for helpful discussions; H. Kimura (Tokyo Institution of Technology) for monoclonal antibodies against H3K9me3 and H3K27me3; K. Kometani (Kyoto University) for advice regarding in vivo B1-8 hi analysis; T. Fujiwara (Tohoku University) for providing the multiple myeloma cell line KMS12PE; T. Yamashita (Tohoku University) and Y. Kurokochi (Tohoku University) for technical support; M. Kikuchi (Tohoku University) for operating the Illumina GAIIx; and T. Yamashita (Keyence) for providing BZ-X800 technical support. This work was supported by Japan Society for the Promotion of Science Indo-Japan Bilateral Joint Research Projects grants and grants-in-aid ( 15H02506 , 16H01295 , 20K07351 , and 18H04021 ) and the Agency for Medical Research and Development (AMED-CREST grant 16gm050001 ). Part of this study was supported by the Biomedical Research Core of the Tohoku University School of Medicine and Tohoku University Center for Gender Equality Promotion . T.K.K. acknowledges support from JNCASR, an India and Sir J.C. Bose National Fellowship, the Department of Science and Technology , and the Government of India. Funding Information: The authors thank S. Tashiro (Hiroshima University), T. Ikura (Kyoto University), A. Muto, and S. Kaypee (Tohoku University) for helpful discussions; H. Kimura (Tokyo Institution of Technology) for monoclonal antibodies against H3K9me3 and H3K27me3; K. Kometani (Kyoto University) for advice regarding in vivo B1-8hi analysis; T. Fujiwara (Tohoku University) for providing the multiple myeloma cell line KMS12PE; T. Yamashita (Tohoku University) and Y. Kurokochi (Tohoku University) for technical support; M. Kikuchi (Tohoku University) for operating the Illumina GAIIx; and T. Yamashita (Keyence) for providing BZ-X800 technical support. This work was supported by Japan Society for the Promotion of Science Indo-Japan Bilateral Joint Research Projects grants and grants-in-aid (15H02506, 16H01295, 20K07351, and 18H04021) and the Agency for Medical Research and Development (AMED-CREST grant 16gm050001). Part of this study was supported by the Biomedical Research Core of the Tohoku University School of Medicine and Tohoku University Center for Gender Equality Promotion. T.K.K. acknowledges support from JNCASR, an India and Sir J.C. Bose National Fellowship, the Department of Science and Technology, and the Government of India. K.O. designed and executed experiments, analyzed data, and wrote the manuscript. M.Y. supported by M.M. assisted with microarray analysis. A.S. helped with purification of the PC4 complex. H.S. performed liquid chromatography-tandem mass spectrometry (LC-MS/MS). H.H. and T.A. assisted with DNA methylation analysis. D.K. J.N. and T.T. assisted with bioinformatics. D.K. executed super-enhancer analysis. R.F. and K.N. managed the Illumina sequencers. T.I. assisted with the mouse in vivo assay. R.S. assisted with mouse immunization analysis. P.B. provided Sub1 flox mice. T.K.K. provided technical advice. T.K.K. and K.I. conceived the project, analyzed data, and provided input to the manuscript. K.I. edited the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = dec,
day = "22",
doi = "10.1016/j.celrep.2020.108517",
language = "English",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}