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1. 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 Hits1276Downloads767 Comment 0

2. 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 Hits1698Downloads474 Comment 0

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