E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation
E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation
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DOI：
10.1523/jneurosci.2840-13.2014
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发表时间：
2014-01-22
影响因子：
5.3
通讯作者：
Casaccia, Patrizia
中科院分区：
文献类型：
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作者：
Magri, Laura;Swiss, Victoria A.;Casaccia, Patrizia
细胞周期退出是少突胶质前体细胞分化为髓鞘细胞的必经步骤。E2F/Rb通路是从增殖向静止转变的关键调节因子，其活性在生理条件下受到高度调节，在肿瘤中则被解除调控。在本文中，我们报道了在啮齿动物OPC分化为发育中的白质束和培养细胞中的少突胶质细胞(OL)的过程中，核E2F1的谱系特异性下降。利用染色质免疫沉淀(ChIP)和大鼠OPC的深度测序，我们确定了细胞周期基因(即cdc2)和染色质成分(即HMGN1、Hmgn2)，包括那些调节DNA甲基化的基因(即uhrf1)，作为E2F1的靶标。验证了E2F1与基因靶点上的染色质的结合，并评估了它们在发育中的白质束和培养的OPC中的表达。与正常脑组织相比，E2F1基因靶标在小鼠胶质瘤(由OPC逆转录病毒转化诱导)中的表达也增加。综上所述，这些数据证实E2F1是一个关键的转录因子，在OPC从增殖到分化的转变过程中调节染色质成分的表达。
Cell cycle exit is an obligatory step for the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating cells. A key regulator of the transition from proliferation to quiescence is the E2F/Rb pathway, whose activity is highly regulated in physiological conditions and deregulated in tumors. In this paper we report a lineage-specific decline of nuclear E2F1 during differentiation of rodent OPC into oligodendrocytes (OLs) in developing white matter tracts and in cultured cells. Using chromatin immunoprecipitation (ChIP) and deep-sequencing in mouse and rat OPCs, we identified cell cycle genes (i.e., Cdc2) and chromatin components (i.e., Hmgn1, Hmgn2), including those modulating DNA methylation (i.e., Uhrf1), as E2F1 targets. Binding of E2F1 to chromatin on the gene targets was validated and their expression assessed in developing white matter tracts and cultured OPCs. Increased expression of E2F1 gene targets was also detected in mouse gliomas (that were induced by retroviral transformation of OPCs) compared with normal brain. Together, these data identify E2F1 as a key transcription factor modulating the expression of chromatin components in OPC during the transition from proliferation to differentiation.