2019 Vol. 10, No. 10

PCGF6 is a member of the transcription-repressing Polycomb group (PcG),and also activates the pluripotency genes. Huang et al.show that PCGF6 is enriched in the superenhancer (SE) regions to activate cell cycle-associated genes by the recruitment of OCT4,depicted in this artwork by a butterfly landed on the vine and visited the flowers, and another butterfly was attracted subsequently.PCGF6 coordinates with OCT4 to regulate SE-promoter interactions, conceptualized here as two positions of vine closing to each other.These findings highlight a novel mechanism of PcG proteins in regulating pluripotency in embryonic stem cells. Cover artwork by Xinyi Liu.Jia Wang,and Xiaona Huang.
Shitsan Pai: the establishment of the first biophysics department in the world
Rui Liu
2019, 10(10): 701-704. doi: 10.1007/s13238-018-0557-0
CRISPR-mediated gene editing to rescue haploinsufficient obesity syndrome
Zhifeng Wang, Liu Yang, Shen Qu, Chao Zhang
2019, 10(10): 705-708. doi: 10.1007/s13238-019-0635-y
Research articles
PCGF6 regulates stem cell pluripotency as a transcription activator via super-enhancer dependent chromatin interactions
Xiaona Huang, Chao Wei, Fenjie Li, Lumeng Jia, Pengguihang Zeng, Jiahe Li, Jin Tan, Tuanfeng Sun, Shaoshuai Jiang, Jia Wang, Xiuxiao Tang, Qingquan Zhao, Bin Liu, Limin Rong, Cheng Li, Junjun Ding
2019, 10(10): 709-725. doi: 10.1007/s13238-019-0629-9
Polycomb group (PcG) ring finger protein 6 (PCGF6), though known as a member of the transcription-repressing complexes, PcG, also has activation function in regulating pluripotency gene expression. However, the mechanism underlying the activation function of PCGF6 is poorly understood. Here, we found that PCGF6 co-localizes to gene activation regions along with pluripotency factors such as OCT4. In addition, PCGF6 was recruited to a subset of the super-enhancer (SE) regions upstream of cell cycle-associated genes by OCT4, and increased their expression. By combining with promoter capture Hi-C data, we found that PCGF6 activates cell cycle genes by regulating SE-promoter interactions via 3D chromatin. Our findings highlight a novel mechanism of PcG protein in regulating pluripotency, and provide a research basis for the therapeutic application of pluripotent stem cells.
Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1
Hongmei Mao, Zaiming Tang, Hua Li, Bo Sun, Mingjia Tan, Shaohua Fan, Yuan Zhu, Yi Sun
2019, 10(10): 726-744. doi: 10.1007/s13238-019-0614-3
The primary cilium is a microtubule-based sensory organelle. The molecular mechanism that regulates ciliary dynamics remains elusive. Here, we report an unexpected finding that MLN4924, a small molecule inhibitor of NEDD8-activating enzyme (NAE), blocks primary ciliary formation by inhibiting synthesis/assembly and promoting disassembly. This is mainly mediated by MLN4924-induced phosphorylation of AKT1 at Ser473 under serum-starved, ciliary-promoting conditions. Indeed, pharmaceutical inhibition (by MK2206) or genetic depletion (via siRNA) of AKT1 rescues MLN4924 effect, indicating its causal role. Interestingly, pAKT1-Ser473 activity regulates both ciliary synthesis/assembly and disassembly in a MLN4924 dependent manner, whereas pAKT-Thr308 determines the ciliary length in MLN4924-independent but VHL-dependent manner. Finally, MLN4924 inhibits mouse hair regrowth, a process requires ciliogenesis. Collectively, our study demonstrates an unexpected role of a neddylation inhibitor in regulation of ciliogenesis via AKT1, and provides a proof-of-concept for potential utility of MLN4924 in the treatment of human diseases associated with abnormal ciliogenesis.
Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer's disease
Wenjuan Wu, Shuwen Du, Wei Shi, Yunlong Liu, Ying Hu, Zuolei Xie, Xinsheng Yao, Zhenyu Liu, Weiwei Ma, Lin Xu, Chao Ma, Yi Zhong
2019, 10(10): 745-759. doi: 10.1007/s13238-019-0641-0
Accelerated forgetting has been identified as a feature of Alzheimer's disease (AD), but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models. Ras-related C3 botulinum toxin substrate 1 (Rac1), a small GTPase, has been shown to regulate active forgetting in Drosophila and mice. Here, we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models. Moreover, amyloid-beta 42 could induce Rac1 activation in cultured cells. The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice, but also significantly contributed to severe memory loss in aged APP/PS1 mice. A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model. Moreover, inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models. Finally, two novel compounds, identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models, were found to be capable of inhibiting Rac1 activity. Thus, multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.
Crystal structure and function of Rbj: A constitutively GTP-bound small G protein with an extra DnaJ domain
Zhengrong Gao, Keke Xing, Chang Zhang, Jianxun Qi, Liang Wang, Shan Gao, Ren Lai
2019, 10(10): 760-763. doi: 10.1007/s13238-019-0622-3
Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects
Jianxia Zhou, Liyuan Jin, Fuping Wang, Yuan Zhang, Bing Liu, Tongbiao Zhao
2019, 10(10): 764-769. doi: 10.1007/s13238-019-0643-y
Low-dose quercetin positively regulates mouse healthspan
Lingling Geng, Zunpeng Liu, Si Wang, Shuhui Sun, Shuai Ma, Xiaoqian Liu, Piu Chan, Liang Sun, Moshi Song, Weiqi Zhang, Guang-Hui Liu, Jing Qu
2019, 10(10): 770-775. doi: 10.1007/s13238-019-0646-8
Correction to: Gene activation in human cells using CRISPR/Cpf1-p300 and CRISPR/Cpf1- SunTag systems
Xin Zhang, Wei Wang, Lin Shan, Le Han, Shufeng Ma, Yan Zhang, Bingtao Hao, Ying Lin, Zhili Rong
2019, 10(10): 776-777. doi: 10.1007/s13238-018-0585-9