The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.
The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.
复制标题
赖氨酸乙酰转移酶激活剂BRPF1通过神经干细胞和祖细胞来控制齿状回的发育。
DOI：
10.1371/journal.pgen.1005034
复制
发表时间：
2015-03
期刊：
影响因子：
4.5
通讯作者：
Yang XJ
中科院分区：
文献类型：
--
作者：
You L;Yan K;Zou J;Zhao H;Bertos NR;Park M;Wang E;Yang XJ
赖氨酸乙酰化是近年来生物体中一种重要的翻译后修饰，但对它在哺乳动物发育和干细胞中的作用知之甚少。含溴结构域和PHD指蛋白1（BRPF 1）是一种多结构域组蛋白结合剂，也是三种赖氨酸乙酰转移酶MOZ、MORF和HBO 1的主激活剂，这三种赖氨酸乙酰转移酶也分别称为KAT 6A、KAT 6B和KAT 7。虽然MOZ和MORF基因在白血病中重排，但MORF基因在前列腺癌和其他癌症以及四种具有智力残疾的遗传性疾病中也发生突变。在这里，我们表明，前脑特异性小鼠Brpf1基因失活导致发育不全的齿状回，包括不发达的suprapyramidal叶片和完全丧失的锥体下叶。我们追踪受损的Sox 2+神经干细胞和Tbr 2+中间神经元祖细胞的发育起源。我们进一步证明，Brpf1损失失调神经元迁移，细胞周期进程和转录控制，从而导致海马异常形态发生。这些结果将组蛋白结合和乙酰化控制与海马发育联系起来，并确定了一种重要的表观遗传调节剂，用于形成齿状回，这是一种对学习，记忆和成人神经发生至关重要的大脑结构。赖氨酸乙酰化是指在蛋白质合成后将乙酰基添加到赖氨酸残基上。关于这种修饰如何在大脑和神经干细胞中发挥作用，人们知之甚少。它由一组称为赖氨酸乙酰转移酶的酶催化。一种称为BRPF 1的新型表观遗传调节因子作为三种不同赖氨酸乙酰转移酶的主激活剂，并且还包含用于组蛋白结合的多个结构域。在这项研究中，我们表明，前脑特定的小鼠Brpf1基因失活导致异常发育的齿状回，海马的关键组成部分。我们追踪受损的神经干细胞和祖细胞的发育起源，并证明Brpf1损失失调的神经元迁移和细胞周期进程在齿状回的发展。这是第一份关于表观遗传调节因子的报告，它的缺失对海马体，特别是齿状回，一个对学习，记忆和成年神经发生至关重要的大脑结构产生了如此深远的影响。
Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis. Lysine acetylation refers to addition of the acetyl group to lysine residues after protein synthesis. Little is known about how this modification plays a role in the brain and neural stem cells. It is catalyzed by a group of enzymes known as lysine acetyltransferases. A novel epigenetic regulator called BRPF1 acts as a master activator of three different lysine acetyltransferases and also contains multiple structural domains for histone binding. In this study, we show that forebrain-specific inactivation of the mouse Brpf1 gene causes abnormal development of the dentate gyrus, a key component of the hippocampus. We trace the developmental origin to compromised neural stem cells and progenitors, and demonstrate that Brpf1 loss deregulates neuronal migration and cell cycle progression during development of the dentate gyrus. This is the first report on an epigenetic regulator whose loss has such a profound impact on the hippocampus, especially the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.
登录
查看更多内容
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
DOI：
10.1523/jneurosci.4185-12.2013
发表时间：
2013-02-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Hodge RD;Garcia AJ 3rd;Elsen GE;Nelson BR;Mussar KE;Reiner SL;Ramirez JM;Hevner RF
通讯作者：
Hevner RF
影响因子：
10.5
作者：
Arnold, Sebastian J.;Huang, Guo-Jen;Groszer, Matthias
通讯作者：
Groszer, Matthias
影响因子：
25
作者：
Favaro, Rebecca;Valotta, Menella;Nicolis, Silvia K.
通讯作者：
Nicolis, Silvia K.
影响因子：
50.3
作者：
Deguchi, K;Ayton, PM;Gilliland, DG
通讯作者：
Gilliland, DG