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Dive into the research topics where Zi-Bing Jin is active.

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Featured researches published by Zi-Bing Jin.


Journal of Cell Science | 2009

In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction

Fumitaka Osakada; Zi-Bing Jin; Yasuhiko Hirami; Hanako Ohashi Ikeda; Teruko Danjyo; Kiichi Watanabe; Yoshiki Sasai; Masayo Takahashi

The use of stem-cell therapy to treat retinal degeneration holds great promise. However, definitive methods of retinal differentiation that do not depend on recombinant proteins produced in animal or Escherichia coli cells have not been devised. Here, we report a defined culture method using low-molecular-mass compounds that induce differentiation of human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells into retinal progenitors, retinal pigment epithelium cells and photoreceptors. The casein kinase I inhibitor CKI-7, the ALK4 inhibitor SB-431542 and the Rho-associated kinase inhibitor Y-27632 in serum-free and feeder-free floating aggregate culture induce retinal progenitors positive for RX, MITF, PAX6 and CHX10. The treatment induces hexagonal pigmented cells that express RPE65 and CRALBP, form ZO1-positive tight junctions and exhibit phagocytic functions. Subsequent treatment with retinoic acid and taurine induces photoreceptors that express recoverin, rhodopsin and genes involved in phototransduction. Both three-factor (OCT3/4, SOX2 and KLF4) and four-factor (OCT3/4, SOX2, KLF4 and MYC) human iPS cells could be successfully differentiated into retinal cells by small-molecule induction. This method provides a solution to the problem of cross-species antigenic contamination in cell-replacement therapy, and is also useful for in vitro modeling of development, disease and drug screening.


PLOS ONE | 2011

Modeling Retinal Degeneration Using Patient-Specific Induced Pluripotent Stem Cells

Zi-Bing Jin; Satoshi Okamoto; Fumitaka Osakada; Kohei Homma; Juthaporn Assawachananont; Yasuhiko Hirami; Takeshi Iwata; Masayo Takahashi

Retinitis pigmentosa (RP) is the most common inherited human eye disease resulting in night blindness and visual defects. It is well known that the disease is caused by rod photoreceptor degeneration; however, it remains incurable, due to the unavailability of disease-specific human photoreceptor cells for use in mechanistic studies and drug screening. We obtained fibroblast cells from five RP patients with distinct mutations in the RP1, RP9, PRPH2 or RHO gene, and generated patient-specific induced pluripotent stem (iPS) cells by ectopic expression of four key reprogramming factors. We differentiated the iPS cells into rod photoreceptor cells, which had been lost in the patients, and found that they exhibited suitable immunocytochemical features and electrophysiological properties. Interestingly, the number of the patient-derived rod cells with distinct mutations decreased in vitro; cells derived from patients with a specific mutation expressed markers for oxidation or endoplasmic reticulum stress, and exhibited different responses to vitamin E than had been observed in clinical trials. Overall, patient-derived rod cells recapitulated the disease phenotype and expressed markers of cellular stresses. Our results demonstrate that the use of patient-derived iPS cells will help to elucidate the pathogenic mechanisms caused by genetic mutations in RP.


Scientific Reports | 2015

Comparison of non-canonical PAMs for CRISPR/Cas9-mediated DNA cleavage in human cells

Yilan Zhang; Xianglian Ge; Fayu Yang; Liping Zhang; Jiayong Zheng; Xuefang Tan; Zi-Bing Jin; Jia Qu; Feng Gu

CRISPR/Cas9 -mediated DNA cleavage (CCMDC) is becoming increasingly used for efficient genome engineering. Proto-spacer adjacent motif (PAM) adjacent to target sequence is one of the key components in the design of CCMDC strategies. It has been reported that NAG sequences are the predominant non-canonical PAM for CCMDC at the human EMX locus, but it is not clear whether it is universal at other loci. In the present study, we attempted to use a GFP-reporter system to comprehensively and quantitatively test the efficiency of CCMDC with non-canonical PAMs in human cells. The initial results indicated that the effectiveness of NGA PAM for CCMDC is much higher than that of other 14 PAMs including NAG. Then we further designed another three pairs of NGG, NGA and NAG PAMs at different locations in the GFP gene and investigated the corresponding DNA cleavage efficiency. We observed that one group of NGA PAMs have a relatively higher DNA cleavage efficiency, while the other groups have lower efficiency, compared with the corresponding NAG PAMs. Our study clearly demonstrates that NAG may not be the universally predominant non-canonical PAM for CCMDC in human cells. These findings raise more concerns over off-target effects in CRISPR/Cas9-mediated genome engineering.


Stem Cells Translational Medicine | 2012

Integration-Free Induced Pluripotent Stem Cells Derived from Retinitis Pigmentosa Patient for Disease Modeling

Zi-Bing Jin; Satoshi Okamoto; Ping Xiang; Masayo Takahashi

We investigated retinitis pigmentosa (RP) caused by a mutation in the gene rhodopsin (RHO) with a patient‐specific rod cell model generated from induced pluripotent stem cells (iPSCs) derived from an RP patient. To generate the iPSCs and to avoid the unpredictable side effects associated with retrovirus integration at random loci in the host genome, a nonintegrating Sendai‐virus vector was installed with four key reprogramming gene factors (POU5F1, SOX2, KLF4, and c‐MYC) in skin cells from an RP patient. Subsequent selection of the iPSC lines was on the basis of karyotype analysis as well as in vitro and in vivo pluripotency tests. Using a serum‐free, chemically defined, and stepwise differentiation method, the expressions of specific markers were sequentially induced in a neural retinal progenitor, a retinal pigment epithelial (RPE) progenitor, a photoreceptor precursor, RPE cells, and photoreceptor cells. In the differentiated rod cells, diffused distribution of RHO protein in cytoplasm and expressions of endoplasmic reticulum (ER) stress markers strongly indicated the involvement of ER stress. Furthermore, the rod cell numbers decreased significantly after successive culture, suggesting an in vitro model of rod degeneration. Thus, from integration‐free patient‐specific iPSCs, RP patient‐specific rod cells were generated in vitro that recapitulated the disease feature and revealed evidence of ER stress in this patient, demonstrating its utility for disease modeling in vitro.


Genetics in Medicine | 2015

Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Xiu-Feng Huang; Fang Huang; Kun-Chao Wu; Juan Wu; Jie Chen; Chi Pui Pang; Fan Lu; Jia Qu; Zi-Bing Jin

Purpose:Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Because of extreme genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined, and there is limited information on genotype–phenotype correlations. The purpose of this study was to elucidate the mutational spectrum and genotype–phenotype correlations of IRD.Methods:We developed a targeted panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, used for exome sequencing. A total of 179 Chinese families with IRD were recruited.Results:In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel mutations (detection rate, 55.3%). Moreover, novel genotype–phenotype correlations were discovered, and phenotypic trends noted. Three cases are reported, including the identification of AHI1 as a novel candidate gene for nonsyndromic retinitis pigmentosa.Conclusion:This study revealed novel genotype–phenotype correlations, including a novel candidate gene, and identified 124 genetic defects within a cohort with IRD . The identification of novel genotype–phenotype correlations and the spectrum of mutations greatly enhance the current knowledge of IRD phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments of IRD patients.Genet Med 17 4, 271–278.


Journal of Medical Genetics | 2008

Identifying Pathogenic Genetic Background of Simplex or Multiplex Retinitis Pigmentosa Patients: A Large-Scale Mutation Screening Study

Zi-Bing Jin; Michiko Mandai; Tomoko Yokota; Kaori Higuchi; Katsuyuki Ohmori; Fumiko Ohtsuki; Shunji Takakura; Toshitaka Itabashi; Yuko Wada; Masayuki Akimoto; Satoro Ooto; Takuya Suzuki; Yasuhiko Hirami; Hanako Ohashi Ikeda; Naoaki Kawagoe; Akio Oishi; Satoshi Ichiyama; Masayo Takahashi; Nagahisa Yoshimura; Shinji Kosugi

Background and purpose: More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance. Methods and results: Since 2003, 52 simplex RP patients, 151 patients from 141 multiplex RP families, and six sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harboured the reported mutations were screened by an efficient denaturing high performance liquid chromatography (dHPLC) based assay. Aberrant fragments were subsequently analysed by automatic sequencing. Twenty-six mutations, including two frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in two sporadic cases and one multiplex family, indicating the possibility of novel digenic patterns. Of the 23 missense mutations, 21 were predicted as deleterious mutations by computational methods using PolyPhen, SIFT, PANTHER, and PMut programs. Conclusion: We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.


PLOS ONE | 2013

Targeted exome sequencing identified novel USH2A mutations in Usher syndrome families.

Xiu-Feng Huang; Ping Xiang; Jie Chen; Dong-Jun Xing; Na Huang; Qingjie Min; Feng Gu; Yi Tong; Chi Pui Pang; Jia Qu; Zi-Bing Jin

Usher syndrome (USH) is a leading cause of deaf-blindness in autosomal recessive trait. Phenotypic and genetic heterogeneities in USH make molecular diagnosis much difficult. This is a pilot study aiming to develop an approach based on next-generation sequencing to determine the genetic defects in patients with USH or allied diseases precisely and effectively. Eight affected patients and twelve unaffected relatives from five unrelated Chinese USH families, including 2 pseudo-dominant ones, were recruited. A total of 144 known genes of inherited retinal diseases were selected for deep exome resequencing. Through systematic data analysis using established bioinformatics pipeline and segregation analysis, a number of genetic variants were released. Eleven mutations, eight of them were novel, in the USH2A gene were identified. Biparental mutations in USH2A were revealed in 2 families with pseudo-dominant inheritance. A proband was found to have triple mutations, two of them were supposed to locate in the same chromosome. In conclusion, this study revealed the genetic defects in the USH2A gene and demonstrated the robustness of targeted exome sequencing to precisely and rapidly determine genetic defects. The methodology provides a reliable strategy for routine gene diagnosis of USH.


Nature Communications | 2014

SLC7A14 linked to autosomal recessive retinitis pigmentosa

Zi-Bing Jin; Xiu-Feng Huang; Ji-Neng Lv; Lue Xiang; Dong-Qing Li; Jiangfei Chen; Changjiang Huang; Jinyu Wu; Fan Lu; Jia Qu

Retinitis pigmentosa (RP) is characterized by degeneration of the retinal photoreceptors and is the leading cause of inherited blindness worldwide. Although few genes are known to cause autosomal recessive RP (arRP), a large proportion of disease-causing genes remain to be revealed. Here we report the identification of SLC7A14, a potential cationic transporter, as a novel gene linked to arRP. Using exome sequencing and direct screening of 248 unrelated patients with arRP, we find that mutations in the SLC7A14 gene account for 2% of cases of arRP. We further demonstrate that SLC7A14 is specifically expressed in the photoreceptor layer of the mammalian retina and its expression increases during postnatal retinal development. In zebrafish, downregulation of slc7a14 expression leads to an abnormal eye phenotype and defective light-induced locomotor response. Furthermore, targeted knockout of Slc7a14 in mice results in retinal degeneration with abnormal ERG response. This suggests that SLC7A14 has an important role in retinal development and visual function.


Genetics in Medicine | 2015

Identification of false-negative mutations missed by next-generation sequencing in retinitis pigmentosa patients: a complementary approach to clinical genetic diagnostic testing

Xiu-Feng Huang; Juan Wu; Ji-Neng Lv; Xiao Zhang; Zi-Bing Jin

Purpose:Retinitis pigmentosa (RP) is a major cause of heritable human blindness with extreme genetic heterogeneity. A large number of causative genes have been defined by next-generation sequencing (NGS). However, due to technical limitations, determining the existence of uncovered or low-depth regions is a fundamental challenge in analyzing NGS data. Therefore, undetected mutations may exist in genomic regions less effectively covered by NGS.Methods:To address this problem, we tested a complementary approach for identifying previously undetected mutations in NGS data sets. The strategy consisted of coverage-based analysis and additional target screening of low-depth regions. Fifty RP patients were analyzed, and none of the mutations found had previously been identified by NGS.Results:Coverage-based analysis indicated that, because of a highly repetitive sequence, the RPGR open reading frame (ORF)15 was located in an uncovered or low-depth region. Through additional screening of ORF15, we identified pathogenic mutations in 14% (7/50) of patients, including four novel mutations first described herein.Conclusion:In brief, we support the need for a complementary approach to identify mutations undetected by NGS, underscoring the power and significance of combining coverage-based analysis with additional target screening of low-depth regions in improving diagnosis of genetic diseases. In addition to its usefulness in RP, this approach is likely applicable to other Mendelian diseases.Genet Med 17 4, 307–311.


Database | 2014

‘RetinoGenetics’: a comprehensive mutation database for genes related to inherited retinal degeneration

Xia Ran; Wei-Jun Cai; Xiu-Feng Huang; Qi Liu; Fan Lu; Jia Qu; Jinyu Wu; Zi-Bing Jin

Inherited retinal degeneration (IRD), a leading cause of human blindness worldwide, is exceptionally heterogeneous with clinical heterogeneity and genetic variety. During the past decades, tremendous efforts have been made to explore the complex heterogeneity, and massive mutations have been identified in different genes underlying IRD with the significant advancement of sequencing technology. In this study, we developed a comprehensive database, ‘RetinoGenetics’, which contains informative knowledge about all known IRD-related genes and mutations for IRD. ‘RetinoGenetics’ currently contains 4270 mutations in 186 genes, with detailed information associated with 164 phenotypes from 934 publications and various types of functional annotations. Then extensive annotations were performed to each gene using various resources, including Gene Ontology, KEGG pathways, protein–protein interaction, mutational annotations and gene–disease network. Furthermore, by using the search functions, convenient browsing ways and intuitive graphical displays, ‘RetinoGenetics’ could serve as a valuable resource for unveiling the genetic basis of IRD. Taken together, ‘RetinoGenetics’ is an integrative, informative and updatable resource for IRD-related genetic predispositions. Database URL: http://www.retinogenetics.org/.

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Lue Xiang

Wenzhou Medical College

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Kun-Chao Wu

Wenzhou Medical College

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Ji-Neng Lv

Wenzhou Medical College

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Chi Pui Pang

The Chinese University of Hong Kong

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Feng Gu

Wenzhou Medical College

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Xue-Bi Cai

Wenzhou Medical College

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Yuqin Wang

Wenzhou Medical College

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