Kular Rupinder K, Cvetanovic Marija, Siferd Steve, Kini Ameet R, Opal Puneet
Davee Department of Neurology and Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
J Biol Chem. 2009 Mar 20;284(12):7783-92. doi: 10.1074/jbc.M806150200. Epub 2009 Jan 9.
Neuronal differentiation is a tightly regulated process characterized by temporal and spatial alterations in gene expression. A number of studies indicate a significant role for histone acetylation in the regulation of genes involved in development. Histone acetylation is regulated by histone deacetylases and histone acetyltransferases. Recent findings suggest that these catalytic activities, in turn, are modulated by yet another set of regulators. Of considerable interest in this context is the possible role of the INHAT (inhibitor of histone acetyltransferase) complex, comprised of a group of acidic proteins that suppress histone acetylation by a novel "histone-masking" mechanism. In this study, we specifically examined the role of the leucine-rich acidic nuclear protein (LANP), a defining member of the INHAT complex whose expression is tightly regulated in neuronal development. We report that depleting LANP in neuronal cell lines promotes neurite outgrowth by inducing changes in gene expression. In addition, we show that LANP directly regulates expression of the neurofilament light chain, an important neuron-specific cytoskeletal gene, by binding to the promoter of this gene and modulating histone acetylation levels. Finally, we corroborated our findings in vivo by demonstrating increased neurite outgrowth in primary neurons obtained from LANP null mice, which is also accompanied by increased histone acetylation at the NF-L promoter. Taken together, these results implicate INHATs as a distinct class of developmental regulators involved in the epigenetic modulation of neuronal differentiation.
神经元分化是一个受到严格调控的过程，其特征在于基因表达的时空变化。多项研究表明组蛋白乙酰化在调控参与发育的基因方面发挥着重要作用。组蛋白乙酰化由组蛋白脱乙酰酶和组蛋白乙酰转移酶调控。最近的研究结果表明，这些催化活性反过来又受到另一组调节因子的调控。在这一背景下，由一组酸性蛋白组成的INHAT（组蛋白乙酰转移酶抑制剂）复合物可能发挥的作用备受关注，该复合物通过一种新型的“组蛋白掩盖”机制抑制组蛋白乙酰化。在本研究中，我们专门研究了富含亮氨酸的酸性核蛋白（LANP）的作用，它是INHAT复合物的一个标志性成员，其表达在神经元发育过程中受到严格调控。我们报告称，在神经元细胞系中耗尽LANP可通过诱导基因表达变化促进神经突生长。此外，我们表明LANP通过与神经丝轻链（一种重要的神经元特异性细胞骨架基因）的启动子结合并调节组蛋白乙酰化水平，直接调控该基因的表达。最后，我们通过证明从LANP基因敲除小鼠获得的原代神经元中神经突生长增加，在体内证实了我们的发现，同时NF-L启动子处的组蛋白乙酰化也增加。综上所述，这些结果表明INHATs是一类独特的发育调节因子，参与神经元分化的表观遗传调控。
