School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Blood. 2012 May 17;119(20):4675-85. doi: 10.1182/blood-2011-12-401117. Epub 2012 Mar 27.
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.
染色质重塑对于 B 细胞分化至关重要。在本研究中，我们探讨了 KAP1（KRAB-ZFP 转录抑制剂的辅因子）在这一过程中的作用。B 淋巴细胞特异性的 Kap1-KO 小鼠表现出成熟 B 细胞数量减少、抗体稳态水平降低以及病毒免疫后中和抗体衰减速度加快。Kap1 缺失的 B 脾细胞的转录组分析显示，PTEN（PI3K 信号的酶拮抗物）和编码 DNA 损伤反应因子、细胞周期调节剂和趋化因子受体的基因上调。ChIP/seq 研究确立了 KAP1 结合在这些基因的启动子附近或附近，并控制着它们的染色质状态。全基因组范围内，KAP1 结合位点缺乏活跃的 B 细胞特异性增强子，富含抑制性组蛋白标记，进一步支持了该分子在体内基因沉默中的作用。可能负责将 KAP1 固定在至少一些这些靶标上的是，离散的 KRAB-ZFP 亚群在 B 淋巴细胞中富集。因此，我们的研究结果揭示了 KRAB/KAP1 介导的表观遗传调控在 B 细胞发育和稳态中的作用。
