Jakobsson Johan, Cordero Maria Isabel, Bisaz Reto, Groner Anna C, Busskamp Volker, Bensadoun Jean-Charles, Cammas Florence, Losson Régine, Mansuy Isabelle M, Sandi Carmen, Trono Didier
School of Life Sciences, National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Neuron. 2008 Dec 10;60(5):818-31. doi: 10.1016/j.neuron.2008.09.036.
KAP1 is an essential cofactor of KRAB-zinc finger proteins, a family of vertebrate-specific epigenetic repressors of largely unknown functions encoded in the hundreds by the mouse and human genomes. Here, we report that KAP1 is expressed at high levels and necessary for KRAB-mediated repression in mature neurons of the mouse brain. Mice deleted for KAP1 in the adult forebrain exhibit heightened levels of anxiety-like and exploratory activity and stress-induced alterations in spatial learning and memory. In the hippocampus, a small number of genes are dysregulated, including some imprinted genes. Chromatin analyses of the promoters of two genes markedly upregulated in knockout mice reveal decreased histone 3 K9-trimethylation and increased histone 3 and histone 4 acetylation. We propose a model in which the tethering of KAP1-associated chromatin remodeling factors via KRAB-ZFPs epigenetically controls gene expression in the hippocampus, thereby conditioning responses to behavioral stress.
KAP1是KRAB锌指蛋白的一个重要辅助因子，KRAB锌指蛋白是一类脊椎动物特有的表观遗传抑制因子，其功能大多未知，在小鼠和人类基因组中有数百个编码。在此，我们报道KAP1在小鼠大脑成熟神经元中高表达，且是KRAB介导的抑制所必需的。在成年前脑缺失KAP1的小鼠表现出焦虑样和探索性活动水平升高，以及应激诱导的空间学习和记忆改变。在海马体中，少数基因失调，包括一些印记基因。对敲除小鼠中两个明显上调基因的启动子进行染色质分析，发现组蛋白3 K9三甲基化减少，组蛋白3和组蛋白4乙酰化增加。我们提出了一个模型，其中通过KRAB锌指蛋白将KAP1相关的染色质重塑因子拴系在一起，从而在表观遗传上控制海马体中的基因表达，进而调节对行为应激的反应。
