The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2.
The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2.
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DOI：
10.1007/s00018-022-04676-6
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发表时间：
2023-01-11
影响因子：
8
通讯作者：
Farinas, Isabel
中科院分区：
文献类型：
--
作者：
Domingo-Muelas, Ana;Manuel Morante-Redolat, Jose;Moncho-Amor, Veronica;Jordan-Pla, Antonio;Perez-Villalba, Ana;Carrillo-Barbera, Pau;Belenguer, German;Porlan, Eva;Kirstein, Martina;Bachs, Oriol;Ferron, Sacri R.;Lovell-Badge, Robin;Farinas, Isabel
关键词：
细胞分化涉及全局基因表达的深刻变化，这些变化通常必须与细胞周期退出协调发生。因为据报道，细胞周期蛋白依赖性激酶抑制剂p27调节成年小鼠大脑室管膜下神经原生态位中神经祖细胞的增殖，但也可以对基因表达产生影响，我们决定从分子水平上分析其在成年神经发生和少突神经发生中的作用。在细胞水平上，我们发现，p27限制了丝裂原撤退后残余的细胞周期蛋白依赖性激酶活性，以拮抗周期，但它不是必不可少的细胞周期退出。通过整合全基因组基因表达和染色质可及性数据，我们发现，p27是巧合地需要抑制许多基因参与从多能性到分化的过渡，包括那些编码神经祖细胞转录因子SOX 2，OLIG 2和ASCL 1。我们的数据揭示了p27与这三个基因中的调控序列的直接关联，以及p27对Sox 2的抑制导致其下游靶点Olig 2和Ascl 1水平降低的额外层级关系。在体内，p27也需要调节神经母细胞和少突胶质祖细胞以谱系依赖性方式及时退出细胞周期所需的适当SOX 2水平。在线版本包含补充材料，可通过10.1007/s 00018 -022-04676-6获得。
Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner. The online version contains supplementary material available at 10.1007/s00018-022-04676-6.
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