4.7 Article

KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function

Journal

BLOOD
Volume 119, Issue 20, Pages 4675-4685

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-12-401117

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Funding

  1. Swiss National Science Foundation
  2. European Research Council
  3. Associazione Italiana per la Ricerca sul Cancro, Milano, Italy

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Chromatin remodeling is fundamental for B-cell differentiation. In the present study, we explored the role of KAP1, the cofactor of KRAB-ZFP transcriptional repressors, in this process. B-lymphoid-specific Kap1-KO mice displayed reduced numbers of mature B cells, lower steady-state levels of Abs, and accelerated rates of decay of neutralizing Abs after viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an up-regulation of PTEN, the enzymatic counteractor of PIK3 signaling, and of genes encoding DNA-damage response factors, cell-cycle regulators, and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to several of these genes and controlled chromatin status at their promoters. Genome wide, KAP1 binding sites lacked active B cell-specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. Our results therefore reveal the role of KRAB/KAP1-mediated epigenetic regulation in B-cell development and homeostasis. (Blood. 2012; 119(20):4675-4685)

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