Journal ArticleDOI
Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2
Zhen Liu,Xiao Li,Jun-Tao Zhang,Yijun Cai,Tian-Lin Cheng,Cheng Cheng,Yan Wang,Chen-Chen Zhang,Yanhong Nie,Zhi-Fang Chen,Wen-Jie Bian,Ling Zhang,Jianqiu Xiao,Bin Lu,Yuefang Zhang,Xiao-Di Zhang,Xiao Sang,Jia-Jia Wu,Xiu Xu,Zhi-Qi Xiong,Feng Zhang,Xiang Yu,Neng Gong,Wenhao Zhou,Qiang Sun,Zilong Qiu +25 more
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TLDR
It is reported that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene, indicating the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.Abstract:
Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.read more
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References
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Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.
Ruthie E. Amir,Ignatia B. Van den Veyver,Mimi Wan,Charles Q. Tran,Uta Francke,Huda Y. Zoghbi +5 more
TL;DR: This study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
Journal ArticleDOI
MeCP2, a key contributor to neurological disease, activates and represses transcription.
Maria H. Chahrour,Sung Yun Jung,Chad A. Shaw,Xiaobo Zhou,Stephen T. C. Wong,Jun Qin,Huda Y. Zoghbi +6 more
TL;DR: It is shown that MeCP2 associates with the transcriptional activator CREB1 at the promoter of an activated target but not a repressed target, and that it can function as both an activator and a repressor of transcription.
Journal ArticleDOI
MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin.
TL;DR: Transient transfection using fusions with the GAL4 DNA binding domain identified a region of MeCP2 that is capable of long-range repression in vivo and suggest a role as a global transcriptional repressor in vertebrate genomes.
Journal ArticleDOI
MapSplice: Accurate mapping of RNA-seq reads for splice junction discovery
Kai Wang,Darshan Singh,Zheng Zeng,S.J. Coleman,Yan Huang,Gleb L. Savich,Xiaping He,Piotr A. Mieczkowski,Sara A. Grimm,Charles M. Perou,James N. MacLeod,Derek Y. Chiang,Jan F. Prins,Jinze Liu +13 more
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