Department of Neuroscience and Genetics and Genomic, Mount Sinai School of Medicine, New York, New York, United States of America.
PLoS One. 2011 Apr 7;6(4):e18088. doi: 10.1371/journal.pone.0018088.
Differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes requires extensive changes in gene expression, which are partly mediated by post-translational modifications of nucleosomal histones. An essential modification for oligodendrocyte differentiation is the removal of acetyl groups from lysine residues which is catalyzed by histone deacetylases (HDACs). The transcriptional targets of HDAC activity within OPCs however, have remained elusive and have been identified in this study by interrogating the oligodendrocyte transcriptome. Using a novel algorithm that allows clustering of gene transcripts according to expression kinetics and expression levels, we defined major waves of co-regulated genes. The initial overall decrease in gene expression was followed by the up-regulation of genes involved in lipid metabolism and myelination. Functional annotation of the down-regulated gene clusters identified transcripts involved in cell cycle regulation, transcription, and RNA processing. To define whether these genes were the targets of HDAC activity, we cultured rat OPCs in the presence of trichostatin A (TSA), an HDAC inhibitor previously shown to inhibit oligodendrocyte differentiation. By overlaying the defined oligodendrocyte transcriptome with the list of 'TSA sensitive' genes, we determined that a high percentage of 'TSA sensitive' genes are part of a normal program of oligodendrocyte differentiation. TSA treatment increased the expression of genes whose down-regulation occurs very early after induction of OPC differentiation, but did not affect the expression of genes with a slower kinetic. Among the increased 'TSA sensitive' genes we detected several transcription factors including Id2, Egr1, and Sox11, whose down-regulation is critical for OPC differentiation. Thus, HDAC target genes include clusters of co-regulated genes involved in transcriptional repression. These results support a de-repression model of oligodendrocyte lineage progression that relies on the concurrent down-regulation of several inhibitors of differentiation.
少突胶质前体细胞（OPC）分化为成熟的少突胶质细胞需要广泛的基因表达变化，部分是由核小体组蛋白的翻译后修饰介导的。少突胶质细胞分化的一个必要修饰是赖氨酸残基上乙酰基的去除，这是由组蛋白去乙酰化酶（HDACs）催化的。然而，OPC 中 HDAC 活性的转录靶标仍然难以捉摸，本研究通过研究少突胶质细胞转录组来鉴定。使用一种新的算法，该算法允许根据表达动力学和表达水平对基因转录本进行聚类，我们定义了主要的共调控基因波。最初的整体基因表达下降后，参与脂质代谢和髓鞘形成的基因上调。下调基因簇的功能注释确定了涉及细胞周期调控、转录和 RNA 加工的转录本。为了确定这些基因是否是 HDAC 活性的靶标，我们在大鼠 OPC 中培养 Trichostatin A（TSA），一种先前显示抑制少突胶质细胞分化的 HDAC 抑制剂。通过将定义的少突胶质细胞转录组与“TSA 敏感”基因列表重叠，我们确定“TSA 敏感”基因的高百分比是少突胶质细胞分化正常程序的一部分。TSA 处理增加了在诱导 OPC 分化后非常早期下调的基因的表达，但不影响动力学较慢的基因的表达。在增加的“TSA 敏感”基因中，我们检测到几个转录因子，包括 Id2、Egr1 和 Sox11，它们的下调对 OPC 分化至关重要。因此，HDAC 靶基因包括参与转录抑制的共调控基因簇。这些结果支持少突胶质细胞谱系进展的去抑制模型，该模型依赖于几个分化抑制剂的同时下调。
