| 1 | LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells显示文摘LIN28 is an RNA binding protein with important roles in early embryo development,stem cell differentiation/re-programming,tumorigenesis and metabolism.Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs,and few have addressed LIN28's role within the nucleus.Here,we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development.Maternal LIN28 expression drops upon exit from the 2-cell stage,and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blas-tocyst stage development,to become dominantly expressed in the cytosol after implantation.In cultured pluripotent stem cells(PSCs),loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes.Mechanistically,LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity,and its loss leads to nucleolar phase separation defects,ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux.LIN28 also resides in a complex containing the nucleolar factor Nucleolin(NCL)and the transcrip-tional repressor TRIM28,and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci,and thus de-repressed Dux and reduced rRNA expression.Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling,translationally inert and anabolically inactive state,which is a part of previously unappreciated 2C-like transcriptional program.These findings elucidate novel roles for nucleolar LIN28 in PSCs,and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development. | Zhen Sun Hua Yu Jing Zhao Tianyu Tan Hongru Pan Yuqing Zhu Lang Chen Cheng Zhang Li Zhang Anhua Lei Yuyan Xu Xianju Bi Xin Huang Bo Gao Longfei Wang Cristina Correia Ming Chen Qiming Sun Yu Feng Li Shen Hao Wu Jianlong Wang Xiaohua Shen George Q.Daley Hu Li Jin Zhang | 2022 | Protein & Cell2022，13，7： | 4 |
| 2 | Homotypic clustering of L1 and B1/Alu repeats compartmentalizes the 3D genome显示文摘Organization of the genome into euchromatin and heterochromatin appears to be evolutionarily conserved and relatively stable during lineage differentiation.In an effort to unravel the basic principle underlying genome folding,here we focus on the genome itself and report a fundamental role for L1(LINE1 or LINE-1)and B1/Alu retrotransposons,the most abundant subclasses of repetitive sequences,in chromatin compartmentalization.We find that homotypic clustering of L1 and B1/Alu demarcates the genome into grossly exclusive domains,and characterizes and predicts Hi-C compartments.Spatial segregation of L1-rich sequences in the nuclear and nucleolar peripheries and B1/Alu-rich sequences in the nuclear interior is conserved in mouse and human cells and occurs dynamically during the cell cycle.In addition,de novo establishment of L1 and B1 nuclear segregation is coincident with the formation of higher-order chromatin structures during early embryogenesis and appears to be critically regulated by L1 and B1 transcripts.Importantly,depletion of L1 transcripts in embryonic stem cells drastically weakens homotypic repeat contacts and compartmental strength,and disrupts the nuclear segregation of L1-or B1-rich chromosomal sequences at genome-wide and individual sites.Mechanistically,nuclear co-localization and liquid droplet formation of L1 repeat DNA and RNA with heterochromatin protein HP1αsuggest a phase-separation mechanism by which L1 promotes heterochromatin compartmentalization.Taken together,we propose a genetically encoded model in which L1 and B1/Alu repeats blueprint chromatin macrostructure.Our model explains the robustness of genome folding into a common conserved core,on which dynamic gene regulation is overlaid across cells. | J.Yuyang Lu Lei Chang Tong Li Ting Wang Yafei Yin Ge Zhan Xue Han Ke Zhang Yibing Tao Michelle Percharde Liang Wang Qi Peng Pixi Yan Hui Zhang Xianju Bi Wen Shao Yantao Hong Zhongyang Wu Runze Ma Peizhe Wang Wenzhi Li Jing Zhang Zai Chang Yingping Hou Bing Zhu Miguel Ramalho-Santos Pilong Li Wei Xie Jie Na Yujie Sun Xiaohua Shen | 2021 | Cell Research2021，31，6： | 1 |
您所在的机构暂未开通此部分的功能，请联系管理员