2018 Vol. 9(4)

The international Human Genome Project (HGP) and China's contribution
Xiaoling Wang, Zhi Xia, Chao Chen, Huanming Yang
2018, 9(4): 317-321. doi: 10.1007/s13238-017-0474-7
Research Articles
Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome
Zeming Wu, Weiqi Zhang, Moshi Song, Wei Wang, Gang Wei, Wei Li, Jinghui Lei, Yu Huang, Yanmei Sang, Piu Chan, Chang Chen, Jing Qu, Keiichiro Suzuki, Juan Carlos Izpisua Belmonte, Guang-Hui Liu
2018, 9(4): 333-350. doi: 10.1007/s13238-018-0517-8
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS-and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations
Zhanping Shi, Yanan Geng, Jiping Liu, Huina Zhang, Liqiang Zhou, Quan Lin, Juehua Yu, Kunshan Zhang, Jie Liu, Xinpei Gao, Chunxue Zhang, Yinan Yao, Chong Zhang, Yi E. Sun
2018, 9(4): 351-364. doi: 10.1007/s13238-017-0450-2
Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSC/NPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSC/NPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSC/NPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Interestingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The Erk/Mapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSC/NPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSC/NPCs and their microenvironment in the context of the aging brain.
NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage
Junhong Guan, Shuyu Yu, Xiaofeng Zheng
2018, 9(4): 365-379. doi: 10.1007/s13238-017-0455-x
NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase η (polη) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to H2O2 stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. Impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-polη interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-polη interaction and blocks polη foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and polη recruitment.
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
2018, 9(4): 380-383. doi: 10.1007/s13238-017-0491-6
Cryo-EM structure of Mycobacterium smegmatis ribosome reveals two unidentified ribosomal proteins close to the functional centers
Zhifei Li, Xueliang Ge, Yixiao Zhang, Lvqin Zheng, Suparna Sanyal, Ning Gao
2018, 9(4): 384-388. doi: 10.1007/s13238-017-0456-9
Ebola virus mucin-like glycoprotein (Emuc) induces remarkable acute inflammation and tissue injury: evidence for Emuc pathogenicity in vivo
Yun-Jia Ning, Zhenyu Kang, Jingjun Xing, Yuan-Qin Min, Dan Liu, Kuan Feng, Manli Wang, Fei Deng, Yiwu Zhou, Zhihong Hu, Hualin Wang
2018, 9(4): 389-393. doi: 10.1007/s13238-017-0471-x

Current Issue

August, 2019

Volume 10, Issue 8

Pages 545-621

About the cover

Utilizing immunocompromised SCID mice after spinal cordinjury (SCI), we performed motor function, electrophysiology,histochemistry analyses and demonstrated that SCID micedisplayed improved CNS functional recovery compared toWT mice after SCI, while SCID mice without injury performedworse in Morris water maze test. Unbiased RNA-sequencinganalysis of spinal cord transcriptomes revealed that SCIDmice had reduced expression of immune function-relatedgenes and heightened expression of neural transmissionrelated genes both before and after SCI, indicating that notonly reduced inflammation after injury but also dampenedsteady-state immune function without injury heightened theneurotransmission program, resulting in better or worsebehavioral outcomes respectively, under pathological orphysiological conditions. This study revealed an interestingand intricate relationship between immune and neuralfunctions.

Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang Beijing 100101, China

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