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

Kyoko Ochiai, Mari Yamaoka, Amrutha Swaminathan, Hiroki Shima, Hitoshi Hiura, Mitsuyo Matsumoto, Daisuke Kurotaki, Jun Nakabayashi, Ryo Funayama, Keiko Nakayama, Takahiro Arima, Tomokatsu Ikawa, Tomohiko Tamura, Roger Sciammas, Philippe Bouvet, Tapas K. Kundu, Kazuhiko Igarashi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number108517
JournalCell Reports
Volume33
Issue number12
DOIs
StatePublished - Dec 22 2020

Keywords

  • cell survival
  • chromatin
  • complex purification
  • human B cell malignancy
  • IKAROS
  • IRF4
  • mature B cell
  • PC4
  • plasma cell differentiation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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