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

Francesca R. Santoni De Sio, Joanna Massacand, Isabelle Barde, Sandra Offner, Andrea Corsinotti, Adamandia Kapopoulou, Karolina Bojkowska, Antonis Dagklis, Marylise Fernandez, Paolo Ghia, James H. Thomas, Daniel Pinschewer, Nicola Harris, Didier Trono

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28 Citations (Scopus)

Abstract

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 steadystate 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.

Original languageEnglish
Pages (from-to)4675-4685
Number of pages11
JournalBlood
Volume119
Issue number20
DOIs
Publication statusPublished - 17 May 2012
Externally publishedYes

Cite this

Santoni De Sio, F. R., Massacand, J., Barde, I., Offner, S., Corsinotti, A., Kapopoulou, A., Bojkowska, K., Dagklis, A., Fernandez, M., Ghia, P., Thomas, J. H., Pinschewer, D., Harris, N., & Trono, D. (2012). KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. Blood, 119(20), 4675-4685. https://doi.org/10.1182/blood-2011-12-401117