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Genome Editing and Its Applications in Model Organisms

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Genomics, Proteomics & Bioinformatics 2015年第6期13卷 336-344页

作者： Dongyuan Ma Feng Liu State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences

Technological advances are important for innovative biological research. Development of molecular tools for DNA manipulation, such as zinc finger nucleases （ZFNs）, transcription activator-like effector nucleases （TALENs）, and the clustered regularly-interspaced short palin- dromic repeat （CR1SPR）/CRISPR-associated （Cas）, has revolutionized genome editing. These approaches can be used to develop potential therapeutic strategies to effectively treat heritable dis- eases. In the last few years, substantial progress has been made in CRISPR/Cas technology, includ- ing technical improvements and wide application in many model systems. This review describes recent advancements in gennme editing with a particular focus on CRISPR/Cas, covering the under- lying principles, technological optimization, and its application in zehrafish and other model organ- isms, disease modeling, and gene therapy used for personalized medicine.

关键词： Genome editingCRISPR/Cas Zebrafish Disease model Gene therapy

The mitophagy receptor FUN14 domaincontaining 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases

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Genes & Diseases 2021年第5期8卷 640-654页

作者： Weilin Zhang State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing100864PR China

Mitochondrial autophagy(mitophagy)is the selective clearance of damaged or incomplete mitochondria by autophagy,which is critical for the functional integrity of the entire mitochondrial network and cell survival.Because dysfunction of mitophagy is closely related to many diseases,it is important to study the specific molecular mechanism and pathophysiological significance of mitophagy.FUN14 domain-containing 1(FUNDC1)is a newly identified mitochon-drial outer membrane protein that induces receptor-mediated mitophagy by its interaction with LC3 during hypoxia.The expression,phosphorylation,regulation and significance of FUNDC1 are reviewed in the context of a large number of pathophysiological conditions.Emerging evidence has demonstrated that levels and phosphorylation states of FUNDC1 are closely related to occur-rence,progression and prognosis of various diseases including heart diseases and cancers,indi-cating that FUNDC1 may serve as a promising biomarker and potential therapeutic target.

关键词： Autophagy Biomarker FUNDC1 Heart diseases Hypoxia Mitochondria Mitochondrial ROS Platelets

Cataract-causing mutation S228P promotes βB1-crystallin aggregation and degradation by separating two interacting loops in C-terminal domain

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Protein & Cell 2016年第7期7卷 501-515页

作者： Liang-Bo Qi Li-Dan Hu Huihui Liu Hai-Yun Li Xiao-Yao Leng Yong-Bin Yan State Key Laboratory of Membrane Biology School of Life Sciences Tsinghua University Beijing 100084 China

β/γ-Crystallins are predominant structural proteins in the cytoplasm of lens fber cells and share a similar fold composing of four Greek-key motifs divided into two domains. Numerous cataract-causing mutations have been identified in various β/γ-crystallins, but the mech- anisms underlying cataract caused by most mutations remains uncharacterized. The S228P mutation in βB1- crystallin has been linked to autosomal dominant con- genital nuclear cataract. Here we found that the S228P mutant was prone to aggregate and degrade in both of the human and E. coli cells. The intracellular S228P aggregates could be redissolved by lanosterol. The S228P mutation modified the refolding pathway of βB1- crystallin by affecting the formation of the dimeric intermediate but not the monomeric intermediate. Compared with native βBl-crystallin, the refolded S228P protein had less packed structures, unquenched Trp fluorophores and increased hydrophobic exposure. The refolded S228P protein was prone to aggregate at the physiological temperature and decreased the protective effect of βB1-crystallin on βA3-crystallin. Molecular dynamic simulation studies indicated that the mutation decreased the subunit binding energy and modified the distribution of surface electrostatic potentials. More importantly, the mutation separated two interacting loops in the C-terminal domain, which shielded the hydrophobic core from solvent in native βB1-crystallin. These two interacting loops are highly conserved in both of the N- and C-terminal domains of all β/γ-crys- tallins. We propose that these two interacting loops play an important role in the folding and structural stability of β/γ-crystallin domains by protecting the hydrophobic core from solvent access.

关键词： β/γ-crystallin cataract-causing mutation,hydrophobic core protein aggregation protein folding

Carcinogens that induce the A：T 〉 T：A nucleotide substitutions in the genome

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Frontiers of Medicine 2018年第2期12卷 236-238页

作者： Guangbiao Zhou Xinchun Zhao State Key Laboratory of Membrane Biology Institute of Zoology Chinese Academy of Sciences Bering 100101 China

Recently, Ng et al. reported that the A：T 〉 T：A substitutions, proposed to be a signature of aristolochic acid （AA） exposure, were detected in 76/98 （78%） of patients with hepatocellular carcinoma （HCC） from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients＇ exposure history is the key to determine the ＂culprit＂ of the A：T 〉 T：A mutations. Apparently, without estimation of the patients＇ exposure history, the conclusion of Ng et al, is unpersuasive and misleading.

关键词： genomic signature carcinogen aristolochic acid tobacco smoke vinyl chloride hepatocellular carcinoma

Biogenesis of autophagosomes from the ERGIC membrane system

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Journal of Genetics and Genomics 2023年第1期50卷 3-6页

作者： Yaping Han Shulin Li Liang Ge The State Key Laboratory of Membrane Biology Tsinghua University-Peking University Joint Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China

Introduction Macroautophagy(hereafter referred as autophagy)is a process of cellular self-degradation.In response to nutrient deprivation or other stimuli,a nascent double-membrane autophagosome,encapsulating intracellular materials or damaged organelles,is generated.The autophagosome is transported toward and eventually fuses with the lysosome(or the vacuole in yeast and plant cells).

关键词： ERGIC COPII vesicle Autophagosome biogenesis Autophagy ERES

BMP signaling in homeostasis, transformation and inflammatory response of intestinal epithelium

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Science China(Life Sciences) 2018年第7期61卷 800-807页

作者： Shan Wang Ye-Guang Chen The State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Life Sciences Tsinghua University

Intestine is the organ for food digestion, nutrient absorption and pathogen defense, in which processes intestinal epithelium plays a central role. Intestinal epithelium undergoes fast turnover, and its homeostasis is regulated by multiple signaling pathways,including Wnt, Notch, Hippo and BMP pathways. BMP signaling has been shown to negatively regulate self-renewal of Lgr5^+ intestinal stem cells, constrains the expansion of intestinal epithelium, therefore attenuating colorectal cancer formation. BMPs and their receptors are expressed in both epithelial and mesenchymal cells, suggesting a two-way interaction between the mesenchyme and epithelium. In this review, we summarize the current understanding of the function of BMP signaling in homeostasis, cancerous transformation and inflammatory response of intestinal epithelium.

关键词： BMP 上皮信号平衡反应肠食物消化相互作用

prpf4 is essential for cell survival and posterior lateral line primordium migration in zebrafish

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Journal of Genetics and Genomics 2018年第8期45卷 443-453页

作者： Yixia Wang Yanchao Han Pengfei Xu Shihui Ding Guangyuan Li Hongbin Jin Yaping Meng Anming Meng Shunji Jia State Key Laboratory of Membrane Biology Tsinghua-Peking Center for Life Sciences School of Life Sciences Tsinghua University

Prpf4 （pre-mRNA processing factor 4）, a key component of spliceosome, plays critical roles in pre-mRNA splicing and its mutations result in retinitis pigmentosa due to photoreceptor defects. In this study, we characterized a zebrafish prpf4t243 mutant harboring a Tol2 transposon-based gene trap cassette in the third intron of the prpf4 gene. Cells in the brain and spinal cord gradually undergo p53-dependent apoptosis after 28 hpf in prpf4t243 mutants, suggesting that a widespread function of prpf4 in neural cell survival. In addition, prpf4 is essential for survival of posterior lateral line primordial （pLLP） cells, prpf4 deficiency perturbs Fgf, Wnt/β-catenin and chemokine signaling pathways and impairs pLLP migration. RNA-Seq analysis suggests that prpf4 deficiency may impair spliceosome assembly, leading to compensatory upregulation of core spliceosomal genes and alteration of pre-mRNA splicing. Taken together, our studies uncover an essential role of prpf4 in pre-mRNA splicing, cell survival and pLLP migration.

关键词： prpf4 Splicing Apoptosisp LLP Zebrafish

Phylogenetic analysis and expression differences of eye-related genes in cavefish genus Sinocyclocheilus

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Integrative Zoology 2021年第3期16卷 354-367页

作者： Yahui ZHAO Zushi HUANG Jinqing HUANG Chunguang ZHANG Fanwei MENG State Key Laboratory of Membrane Biology State Key Laboratory of Integrated Pest ManagementKey Laboratory of ZoologicalSystematics and EvolutionInstitute of ZoologyChinese Academy of SciencesBeijingChina Faculty of Basic Medical Sciences Guilin Medical UniversityGuilinChina

The adaptive evolution of visual systems has been observed in many cavefish.However,little is known about the molecular mechanisms underlying these adaptations,which include regressive changes such as eye degeneration.Here,we analyzed phylogenetic and expression patterns of 6 eye-related genes(crx,foxg1b,opn1sw2,otx2,rho and sox2)in 12 Sinocyclocheilus species from China,including 8 stygobionts and 4 stygophiles,and examined photoreceptor cell morphology of these species.Those eye-degenerated species of Sinocyclocheilus were polyphyletic and showed different degrees of photoreceptor defects in responses to cave environments.The eye loss and degeneration are the result of convergent evolution.Although S.anophthalmus grouped with the eye-normal species,it displayed not only a high degree of eye degeneration but also significant expression differences in eyerelated genes compared with the eye-normal species.The gene foxg1b,which was determined to be under positive selection,might play an important role in the process of eye degeneration in S.anophthalmus based on differential expression.Eye-related gene expression and selection may have contributed to the polyphyly of the cave species.We examined gene expression and duplication in 6 eye-related genes and revealed that these genes displayed considerable diversity in relative expression in Sinocyclocheilus fishes.Otx2 and sox2 were significantly up-regulated in individual cave species,while the other 4 genes(crx,foxg1b,opn1sw2 and rho)were significantly down-regulated.These findings provide a valuable resource for elucidating molecular mechanisms associated with visual system evolution in cavefish.

关键词： cavefish convergent evolution eye degeneration gene duplication retina

Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives

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Zoological Research 2022年第6期43卷 1026-1040页

作者： Zhi-Ya Chen Yan Zhang State Key Laboratory of Membrane Biology College of Life SciencesPeking UniversityBeijing 100871China

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer’s disease(AD)have been made and multifarious novel therapeutic approaches have been developed,AD remains an incurable disease.Evidence shows that AD neuropathology occurs decades before clinical presentation.AD is divided into three stages:preclinical stage,mild cognitive impairment(MCI),and AD dementia.In the natural world,some animals,such as non-human primates(NHPs)and canines,can develop spontaneous AD-like dementia.However,most animals do not develop AD.With the development of transgenic techniques,both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods.Most AD research focuses on early-onset familial AD(FAD)because FAD is associated with specific genetic mutations.However,there are no well-established late-onset sporadic AD(SAD)animal models because SAD is not directly linked to any genetic mutation,and multiple environmental factors are involved.Moreover,the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages.This review summarizes the common models used to study AD,from yeast to NHP models,and discusses the different applications,evaluation methods,and challenges related to AD animal models,as well as prospects for the evolution of future studies.

关键词： Alzheimer’s disease Animal models Neuroinflammation Amyloid-β Tau protein