title: KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function.
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.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Santoni de Sio
authors.forename: Joanna
authors.initials: J
authors.lastname: Massacand
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barde
authors.forename: Sandra
authors.initials: S
authors.lastname: Offner
authors.forename: Andrea
authors.initials: A
authors.lastname: Corsinotti
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.forename: Karolina
authors.initials: K
authors.lastname: Bojkowska
authors.forename: Antonis
authors.initials: A
authors.lastname: Dagklis
authors.forename: Marylise
authors.initials: M
authors.lastname: Fernandez
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: James H
authors.initials: JH
authors.lastname: Thomas
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinschewer
authors.forename: Nicola
authors.initials: N
authors.lastname: Harris
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics / Q000276:immunology / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks / Q000235:genetics / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D001426:Bacterial Proteins; D002843:Chromatin; D008164:Luminescent Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C054562:yellow fluorescent protein, Bacteria; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28