Histone acetyltransferase KAT2A modulates neural stem cell differentiation and proliferation by inducing degradation of the transcription factor PAX6.
Histone acetyltransferase KAT2A modulates neural stem cell differentiation and proliferation by inducing degradation of the transcription factor PAX6.
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DOI：
10.1016/j.jbc.2023.103020
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发表时间：
2023-03
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Dong Z;He W;Lin G;Chen X;Cao S;Guan T;Sun Y;Zhang Y;Qi M;Guo B;Zhou Z;Zhuo R;Wu R;Liu M;Liu Y
神经干细胞（NSCs）的增殖和分化依赖于参与细胞命运决定的转录因子的正确表达和翻译后修饰。需要进一步表征才能将修饰酶与其转录因子底物在调节这些过程中联系起来。在这里，我们证明，抑制KAT 2A，组蛋白乙酰转移酶，导致斑马鱼胚胎发育中的小眼睛表型，这与斑马鱼眼睛中神经干细胞的增殖和凋亡增强有关。我们证实了这种表型是由PAX 6蛋白水平升高介导的。我们进一步验证了KAT 2A在蛋白水平上对培养的大鼠大脑皮层神经干细胞中的PAX 6负调控。我们发现PAX 6是KAT 2A的一种新的乙酰化底物，PAX 6的乙酰化促进了其由E3连接酶RNF 8介导的泛素化，从而促进了PAX 6的降解。我们的研究表明，KAT 2A抑制导致加速增殖，延迟分化或凋亡，这取决于PAX 6剂量的背景。因此，KAT 2A/PAX 6轴在维持神经干细胞自我更新和分化之间的平衡中起着至关重要的作用。
Neural stem cells (NSCs) proliferation and differentiation rely on proper expression and posttranslational modification of transcription factors involved in the determination of cell fate. Further characterization is needed to connect modifying enzymes with their transcription factor substrates in the regulation of these processes. Here, we demonstrated that the inhibition of KAT2A, a histone acetyltransferase, leads to a phenotype of small eyes in the developing embryo of zebrafish, which is associated with enhanced proliferation and apoptosis of NSCs in zebrafish eyes. We confirmed that this phenotype is mediated by the elevated level of PAX6 protein. We further verified that KAT2A negatively regulates PAX6 at the protein level in cultured neural stem cells of rat cerebral cortex. We revealed that PAX6 is a novel acetylation substrate of KAT2A and the acetylation of PAX6 promotes its ubiquitination mediated by the E3 ligase RNF8 that facilitated PAX6 degradation. Our study proposes that KAT2A inhibition results in accelerated proliferation, delayed differentiation, or apoptosis, depending on the context of PAX6 dosage. Thus, the KAT2A/PAX6 axis plays an essential role to keep a balance between the self-renewal and differentiation of NSCs.
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影响因子：
3.7
作者：
Martínez-Cerdeño V;Lemen JM;Chan V;Wey A;Lin W;Dent SR;Knoepfler PS
通讯作者：
Knoepfler PS
影响因子：
16.2
作者：
Mi D;Carr CB;Georgala PA;Huang YT;Manuel MN;Jeanes E;Niisato E;Sansom SN;Livesey FJ;Theil T;Hasenpusch-Theil K;Simpson TI;Mason JO;Price DJ
通讯作者：
Price DJ
影响因子：
3.2
作者：
Ahmed, Sohail;Gan, HuiTheng;Yu, Yuan Hong
通讯作者：
Yu, Yuan Hong
影响因子：
64.8
作者：
Palmer, TD;Schwartz, PH;Gage, FH
通讯作者：
Gage, FH
影响因子：
13.9
作者：
Kriegstein A;Alvarez-Buylla A
通讯作者：
Alvarez-Buylla A