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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 Hits1376Downloads807 Comment 0

2. chinaXiv:201605.01401 [pdf]

Pro-inflammatory Macrophages suppress PPAR gamma activity in Adipocytes via S-nitrosylation

Yin, Ruiying; Fang, Li; Li, Yingjia; Wang, Nanping; Yin, Ruiying; Fang, Li; Li, Yingjia; Wang, Nanping; Xue, Peng; Li, Yazi; Chen, Chang; Guan, Youfei; Wang, Nanping; Chang, Yongsheng; Chang, Yongsheng
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a ligand-activated nuclear receptor and plays an essential role in insulin signaling. Macrophage infiltration into adipose tissue is a character of metabolic inflammation and closely related to insulin resistance in type 2 diabetes. The mechanism by which pro-inflammatory macrophages cause insulin resistance remains to be elucidated. Here we showed that coculture with macrophages significantly suppressed the transcriptional activity of PPAR gamma on its target genes in 3T3-L1 preadipocytes and diabetic primary adipocytes, depending on inducible nitric oxide synthase (iNOS). We further showed that PPAR gamma underwent S-nitrosylation in response to nitrosative stress. Mass-spectrometry and site-directed mutagenesis revealed that S-nitrosylation at cysteine 168 was responsible for the impairment of PPAR gamma function. Extended exposure to NO instigated the proteasome-dependent degradation of PPAR gamma. Consistently, in vivo evidence revealed an association of the decreased PPAR gamma protein level with increased macrophage infiltration in visceral adipose tissue (VAT) of obese diabetic db/db mice. Together, our results demonstrated that pro-inflammatory macrophages suppressed PPAR gamma activity in adipocytes via S-nitrosylation, suggesting a novel mechanism linking metabolic inflammation with insulin resistance. (C) 2015 Elsevier Inc. All rights reserved.

submitted time 2016-05-12 Hits686Downloads456 Comment 0

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