KAP1 regulates gene networks controlling B lymphoid cell differentiation and function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Francesca Santoni de Sio
PROVIDER: E-GEOD-36880 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor 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 a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided 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. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis. Follicular (FO) and Transcriptional 2 Follicular Progenitor (T2-FP) B cells were sorted out from 3 CD19-Cre/Kap1flox (KAP1 KO in the B lineage) mice and 3 wt/Kap1flox littermate controls
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Project description:Chromatin remodeling is fundamental for B cell differentiation. Here, we explored the role in this process of KAP1, the cofactor of KRAB-ZFP transcriptional repressors. B lymphoid-specific Kap1 knockout mice displayed reduced numbers of mature B cells, lower steady-state levels of antibodies and accelerated rates of decay of neutralizing antibodies following viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an upregulation of PTEN, the enzymatic counter-actor 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 a number of these genes, and controlled chromatin status at their promoters. Genome-wide, KAP1-binding sites avoided 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. This work thus reveals the role of KRAB/KAP1-mediated epigenetic regulation in B cell development and homeostasis. Examination of KAP1 binding sites and H3K9me3 enriched regions in KAP1 wild type and KO mouse B splenocytes.
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Project description:The modulation of chromatin status at specific genomic loci controls lymphoid differentiation. Here, we investigated the role played in this process by KAP1, the universal cofactor of KRAB-containing Zinc Finger Proteins (KRAB-ZFPs), a tetrapod-restricted family of transcriptional repressors. T cell-specific Kap1 knockout mice displayed a significant expansion of immature thymocytes and imbalances in the ratios of mature T cells in the thymus and the spleen, with impaired responses to TCR stimulation. Transcriptome and chromatin studies revealed that KAP1 directly controls the expression of a number of genes involved in TCR and cytokine signalling, among which Traf1 and FoxO1, and is strongly associated with cis-acting regulatory elements marked by the H3K9me3 repressive mark on the genome of thymic T cells. Likely responsible for tethering KAP1 to at least part of its genomic targets, a small number of KRAB/ZFPs are selectively expressed in T lymphoid cells. These results reveal the so far unsuspected yet important role of KRAB/KAP1-mediated epigenetic regulation in T lymphocyte differentiation and activation. Cells were harvested form the thymus of 3 CD4-Cre/Kap1flox (KAP1 KO in the T lineage) mice and 3 wt/Kap1flox littermate controls
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