P53 and H3K4me2 activate N6‐methylated LncPGCAT‐1 to regulate primordial germ cell formation via MAPK signaling
P53 and H3K4me2 activate N6‐methylated LncPGCAT‐1 to regulate primordial germ cell formation via MAPK signaling
复制标题
P53 和 H3K4me2 激活 N6-甲基化 LncPGCAT-1，通过 MAPK 信号传导调节原始生殖细胞的形成
DOI：
10.1002/jcp.29805
复制
发表时间：
2020-05
影响因子：
5.6
通讯作者：
Bichun Li
中科院分区：
文献类型：
--
作者：
Qisheng Zuo;Jing Jin;Kai Jin;Jing Zhou;Changhua Sun;Jiuzhou Song;Guohong Chen;Yani Zhang;Bichun Li
长链非编码RNA（lncRNA）参与了原始生殖细胞（PGCs）的形成，然而，其关键lncRNA的身份和PGCs形成的分子机制尚不清楚。在这里，我们通过对胚胎干细胞、PGCs和精原干细胞（SSC）的RNA测序，鉴定出一种关键的候选lncRNA（lncRNA PGC transcript-1，LncPGCAT-1）。功能实验证实，LncPGCAT-1通过上调Cvh和C-kit的表达，同时下调多能性（Nanog），在体外和体内正调控PGCs的形成;体内生殖嵴PAS染色也显示，干扰LncPGCAT-1可显著减少生殖嵴中PGCs的数量，而过表达LncPGCAT-1则相反。荧光素酶报告基因检测结合CHIP-qPCR的结果显示LncPGCAT-1的表达受转录因子P53和高水平H3 K4 me 2的促进。从机制上讲，荧光素酶报告基因试验证实，丝裂原活化蛋白激酶1（MAPK 1）是LncPGCAT-1和gga-mir-1591的靶基因。在ceRNA系统中，LncPGCAT-1的高水平N6甲基化增强了LncPGCAT-1对gga‐mir‐1591的吸附能力。gga‐mir‐1591的吸附通过缓解gga‐mir‐1591依赖性的MAPK 1表达抑制来激活MAPK 1/ERK信号级联。此外，LncPGCAT-1与白细胞介素增强子结合因子3（IL F3）相互作用，调节P53的泛素化和JNK的磷酸化。与ILF 3的相互作用导致LncPGCAT-1的正性自我反馈调节和JNK信号转导的激活，最终促进PGC的形成。总之，这项研究扩展了我们对lncRNA在PGC发展中的功能和分子机制的认识。
Long noncoding RNAs (lncRNAs) participate in the formation of primordial germ cells (PGCs); however, the identity of the key lncRNAs and the molecular mechanisms responsible for the formation of PGCs remain unknown. Here, we identify a key candidate lncRNA (lncRNA PGC transcript‐1, LncPGCAT‐1) via RNA sequencing of embryonic stem cells, PGCs, and Spermatogonial stem cells (SSCs). Functional experiments confirmed that LncPGCAT‐1 positively regulated the formation of PGCs by elevating the expression of Cvh and C‐kit while downregulating the pluripotency(Nanog) in vitro and in vivo; PAS staining of genital ridges in vivo also showed that interference with LncPGCAT‐1 can significantly reduce the number of PGCs in genital ridges, while overexpression of LncPGCAT‐1 had the opposite result. The result of luciferase reporter assay combined with CHIP‐qPCR showed that the expression of LncPGCAT‐1 was promoted by the transcription factor P53 and high levels of H3K4me2. Mechanistically, the luciferase reporter assay confirmed that mitogen‐activated protein kinase 1 (MAPK1) was the target gene of LncPGCAT‐1 and gga‐mir‐1591. In the ceRNA system, high levels of N6 methylation of LncPGCAT‐1 enhanced the adsorption capacity of LncPGCAT‐1 for gga‐mir‐1591. Adsorption of gga‐mir‐1591 activated the MAPK1/ERK signaling cascade by relieving the gga‐mir‐1591‐dependent inhibition of MAPK1 expression. Moreover, LncPGCAT‐1 interacted with interleukin enhancer binding factor 3 (ILF3) to regulate the ubiquitination of P53 and phosphorylation of JNK. Interaction with ILF3 resulted in positive self‐feedback regulation of LncPGCAT‐1 and activation of JNK signaling, ultimately promoting PGC formation. Altogether, the study expands our knowledge of the function and molecular mechanisms of lncRNAs in PGC development.
登录
查看更多内容
NICD介导的Notch转导调节鸡原始生殖细胞和精原干细胞的不同命运
影响因子：
7.5
作者：
左其生;张晨;靳锴;金晶;孙长花;Mahmoud F. Ahmed;宋九州;张亚妮;陈国宏;李碧春
通讯作者：
李碧春
影响因子：
2.7
作者：
Farini, D;Scaldaferri, ML;De Felici, M
通讯作者：
De Felici, M
影响因子：
64.5
作者：
Kim, YK;Furic, L;Maquat, LE
通讯作者：
Maquat, LE
影响因子：
64.5
作者：
Deshpande, G;Swanhart, L;Schedl, P
通讯作者：
Schedl, P
影响因子：
10.5
作者：
Lawson, KA;Dunn, NR;Hogan, BLM
通讯作者：
Hogan, BLM