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1. chinaXiv:201605.01735 [pdf]

PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype

Duan, Shunlei; Yuan, Guohong; Ren, Ruotong; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Liu, Guang-Hui; Liu, Xiaomeng; Li, Jingyi; Tang, Fuchou; Ren, Ruotong; Bai, Ruijun; Liu, Guang-Hui; Ren, Ruotong; Bai, Ruijun; Qu, Jing; Zhang, Weizhou; Wu, Jun
Subjects: Biology >> Biophysics

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficientmice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

submitted time 2016-05-15 Hits1233Downloads521 Comment 0

2. chinaXiv:201605.01529 [pdf]

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Zhang, Weiqi; Wang, Ping; Zhou, Junzhi; Ren, Ruotong; Xu, Xiuling; Yuan, Tingting; Yang, Jiping; Li, Ying; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Chen, Chang; Yang, Fuquan; Liu, Guang-Hui; Li, Jingyi; Liu, Xiaomeng; Tang, Fuchou; Suzuki, Keiichiro; Ocampo, Alejandro
Subjects: Biology >> Biophysics

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1 alpha and nuclear lamina-heterochromatin anchoring protein LAP2 beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

submitted time 2016-05-12 Hits797Downloads489 Comment 0

3. chinaXiv:201605.01464 [pdf]

Regenerative medicine: targeted genome editing in vivo

Wang, Lixia; Liu, Guang-Hui; Wu, Jun; Belmonte, Juan Carlos Izpisua; Fang, Weiwei; Liu, Guang-Hui; Liu, Guang-Hui
Subjects: Biology >> Biophysics >> Cell Biology

The CRISPR/Cas system has proven to be a powerful gene editing tool both in vitro and in vivo. A recent flurry of studies of in vivo gene editing using the CRISPR/Cas system bring bright prospects in creating animal models and targeted gene therapy of human genetic diseases.

submitted time 2016-05-12 Hits901Downloads536 Comment 0

4. chinaXiv:201605.01385 [pdf]

CRISPR/Cas9 and TALE: beyond cut and paste

Deng, Liping; Ren, Ruotong; Liu, Guang-Hui; Wu, Jun; Suzuki, Keiichiro; Belmote, Juan Carlos Izpisua; Liu, Guang-Hui; Liu, Guang-Hui
Subjects: Biology >> Biophysics >> Cell Biology

Nuclease-based genome editing has proven to be a powerful and promising tool for disease modeling and gene therapy. Recent advances in CRISPR/Cas and TALE indicate that they could also be used as a targeted regulator of gene expression, as well as being utilized for illuminating specific chromosomal structures or genomic regions.

submitted time 2016-05-12 Hits532Downloads326 Comment 0

5. chinaXiv:201605.01375 [pdf]

Characterization of a novel mouse model with genetic deletion of CD177

Xie, Qing; Li, Xiangrui; Xie, Qing; Parlet, Corey; Borcherding, Nicholas; Kolb, Ryan; Li, Wei; Tygrett, Lorraine; Waldschmidt, Thomas; Olivier, Alicia; Zhang, Weizhou; Klesney-Tait, Julia; Keck, Kathy; Chen, Songhai; Liu, Guang-Hui; Liu, Guang-Hui
Subjects: Biology >> Biophysics >> Cell Biology

Neutrophils play an essential role in the innate immune response to infection. Neutrophils migrate from the vasculature into the tissue in response to infection. Recently, a neutrophil cell surface receptor, CD177, was shown to help mediate neutrophil migration across the endothelium through interactions with PECAM1. We examined a publicly available gene array dataset of CD177 expression from human neutrophils following pulmonary endotoxin instillation. Among all 22,214 genes examined, CD177 mRNA was the most upregulated following endotoxin exposure. The high level of CD177 expression is also maintained in airspace neutrophils, suggesting a potential involvement of CD177 in neutrophil infiltration under infectious diseases. To determine the role of CD177 in neutrophils in vivo, we constructed a CD177-genetic knockout mouse model. The mice with homozygous deletion of CD177 have no discernible phenotype and no significant change in immune cells, other than decreased neutrophil counts in peripheral blood. We examined the role of CD177 in neutrophil accumulation using a skin infection model with Staphylococcus aureus. CD177 deletion reduced neutrophil counts in inflammatory skin caused by S. aureus. Mechanistically we found that CD177 deletion in mouse neutrophils has no significant impact in CXCL1/KC- or fMLP-induced migration, but led to significant cell death. Herein we established a novel genetic mouse model to study the role of CD177 and found that CD177 plays an important role in neutrophils.

submitted time 2016-05-12 Hits505Downloads308 Comment 0

6. chinaXiv:201605.01363 [pdf]

Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing

Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro; Luo, Jinping; Sugawara, Atsushi; Okamura, Daiji; Wu, Jun; Lam, David; Esteban, Concepcion Rodriguez; Sancho-Martinez, Ignacio; Belmonte, Juan Carlos Izpisua; Bacman, Sandra R.; Williams, Sion L.; Moraes, Carlos T.; Tsunekawa, Yuji; Xiong, Xiong; Zhao, Huimin; Montserrat, Nuria; Liu, Guang-Hui; Liu, Guang-Hui
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

Mitochondrial diseases include a group of maternally inherited genetic disorders caused by mutations in mtDNA. In most of these patients, mutated mtDNA coexists with wild-type mtDNA, a situation known as mtDNA heteroplasmy. Here, we report on a strategy toward preventing germline transmission of mitochondrial diseases by inducing mtDNA heteroplasmy shift through the selective elimination of mutated mtDNA. As a proof of concept, we took advantage of NZB/BALB heteroplasmic mice, which contain two mtDNA haplotypes, BALB and NZB, and selectively prevented their germline transmission using either mitochondria-targeted restriction endonucleases or TALENs. In addition, we successfully reduced human mutated mtDNA levels responsible for Leber's hereditary optic neuropathy (LHOND), and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in mammalian oocytes using mitochondria-targeted TALEN (mito-TALENs). Our approaches represent a potential therapeutic avenue for preventing the trans-generational transmission of human mitochondrial diseases caused by mutations in mtDNA.

submitted time 2016-05-12 Hits1358Downloads319 Comment 0

7. chinaXiv:201605.00772 [pdf]

Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs

Fu, Lina; Xu, Xiuling; Ren, Ruotong; Zhang, Weiqi; Yang, Jiping; Ren, Xiaoqing; Wang, Si; Zhao, Yang; Liu, Guang-Hui; Ren, Ruotong; Zhang, Weiqi; Liu, Guang-Hui; Qu, Jing; Wu, Jun; Belmonte, Juan Carlos Izpisua; Wu, Jun; Sun, Liang; Yang, Ze; Yu, Yang; Qiao, Jie
Subjects: Biology >> Biophysics >> Cell Biology

Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patient-specific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.

submitted time 2016-05-05 Hits530Downloads303 Comment 0

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