Hirano Kazumi, Namihira Masakazu
Molecular Neurophysiology Research Group, Biomedical Research Institute, The National Institute of Advanced Industrial Science and Technology (AIST), Japan.
Stem Cells. 2016 Jul;34(7):1872-82. doi: 10.1002/stem.2362. Epub 2016 Mar 27.
Histone-modifying enzymes dynamically regulate the chromatin status and have been implicated in the fate specification of stem cells, including neural stem cells (NSCs), which differentiate into three major cell types: neurons, astrocytes, and oligodendrocytes. Lysine-specific demethylase 1 (LSD1, also known as KDM1A) catalyzes the demethylation of H3K4me1/2 and H3K9me1/2, and it was recently suggested that functional disruption of LSD1 links to various human diseases. However, the mechanism by which LSD1 regulates human neural development remains unclear. Here, we present evidence that specific inhibition of LSD1 suppresses the neurogenesis of cultured human fetal NSCs (hfNSCs) isolated from the human fetal neocortex. Notably, we found that LSD1 directly associates with the promoter of the HEYL gene, and controls the demethylation of H3K4me2, which is accompanied by repression of HEYL expression during hfNSC neuronal differentiation. Furthermore, we also showed that HEYL expression is sufficient to inhibit the neuronal differentiation of hfNSCs. This mechanism seems to be primate-specific because mouse NSCs do not exhibit the LSD1 inhibitor-induced upregulation of Heyl. Our findings suggest that LSD1 plays an important role in primate neurogenesis and may contribute to the characterization of an evolved primate brain. Stem Cells 2016;34:1872-1882.
组蛋白修饰酶动态调节染色质状态，并与包括神经干细胞（NSC）在内的干细胞命运决定有关，神经干细胞可分化为三种主要细胞类型：神经元、星形胶质细胞和少突胶质细胞。赖氨酸特异性去甲基化酶1（LSD1，也称为KDM1A）催化H3K4me1/2和H3K9me1/2的去甲基化，最近有研究表明LSD1的功能破坏与多种人类疾病有关。然而，LSD1调节人类神经发育的机制仍不清楚。在此，我们提供证据表明，特异性抑制LSD1可抑制从人类胎儿新皮质分离的培养人类胎儿神经干细胞（hfNSC）的神经发生。值得注意的是，我们发现LSD1直接与HEYL基因的启动子结合，并控制H3K4me2的去甲基化，这伴随着hfNSC神经元分化过程中HEYL表达的抑制。此外，我们还表明HEYL表达足以抑制hfNSC的神经元分化。这种机制似乎是灵长类动物特有的，因为小鼠神经干细胞没有表现出LSD1抑制剂诱导的Heyl上调。我们的研究结果表明，LSD1在灵长类动物神经发生中起重要作用，可能有助于对进化的灵长类动物大脑进行特征描述。《干细胞》2016年；34：1872 - 1882。
