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

Santoni de Sio, Francesca R. and Massacand, Joanna and Barde, Isabelle and Offner, Sandra and Corsinotti, Andrea and Kapopoulou, Adamandia and Bojkowska, Karolina and Dagklis, Antonis and Fernandez, Marylise and Ghia, Paolo and Thomas, James H. and Pinschewer, Daniel and Harris, Nicola and Trono, Didier. (2012) KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. Blood, 119 (20). pp. 4675-4685.

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Experimental Virology (Pinschewer)
UniBasel Contributors:Pinschewer, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Hematology
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:15 Dec 2020 12:47
Deposited On:15 Dec 2020 12:47

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