KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function.
Blood, 2012/5/17;119(20):4675-85.
Santoni de Sio FR[1], Massacand J, Barde I, Offner S, Corsinotti A, Kapopoulou A, Bojkowska K, Dagklis A, Fernandez M, Ghia P, Thomas JH, Pinschewer D, Harris N, Trono D
Affiliations
PMID: 22452978DOI: 10.1182/blood-2011-12-401117
Impact factor: 25.476
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 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.
MeSH terms
Animals; Antibody Formation; B-Lymphocytes; Bacterial Proteins; Cell Differentiation; Chromatin; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Luminescent Proteins; Lymphocyte Count; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microarray Analysis; Nuclear Proteins; Repressor Proteins; Tripartite Motif-Containing Protein 28
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