Brain-specific transcriptome analysis in MECP2 transgenic monkeys
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ABSTRACT:
ORGANISM(S): Macaca fascicularis
PROVIDER: GSE57974 | GEO | 2015/11/25
SECONDARY ACCESSION(S): PRJNA248642
REPOSITORIES: GEO
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Project description:We have performed gene expression profiling of the MECP2 transgenic monkey, taking advantage of recently completed genome sequencing for the cynomolgus monkey. We found interesting changes in the pattern of alternative splicing of many genes, including genes coding synaptic proteins (e.g., neurexin-3 and Shank-3) and metabolism-related proteins, as compared to the wild-type monkey. This study provides important information for understanding the impact of disease-related gene on brain development. Examination of transcriptome in brain tissues of wild-type and MECP2 transgenic monkeys.
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Project description:We report Transcription Activator-like Effector Nucleases (TALEN)-mediated mutagenesis of the Rett Syndrome gene, methyl-CpG binding protein 2 (Mecp2), in nonhuman primates (NHPs). Microinjection of Mecp2-targeting TALEN plasmids into rhesus and cynomolgus zygotes caused 40-50% of the embryos harboring mutations when examined beyond 8-cell stage. The surrogate pregnancy rates were 28.6% (2/7) and 16.7% (1/6) for rhesus and cynomolgus, respectively. The 2 rhesus surrogates went through miscarriage at 30- and 63/64-days of gestation. Analyses of two 63/64-day-old liter-mate embryos indicated both were male and carried MeCP2 mutations, yet chimeric. Mutation rate was higher in one embryonic brain than the other. RNA sequencing and anatomical analyses indicated that the brain with higher-degree mutations was underdeveloped, which, together with mid-gestation-stage male lethality likely recapitulate the disease. One live delivery of a female cynomolgus monkey occurred after 162 days of gestation, with abundant mutagenesis in peripheral tissues examined. We conclude that TALEN-mediated mutagenesis greatly facilitates disease modeling in NHPs.
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Project description:Cynomolgus monkeys are well-established translational models for biomedical research and drug testing. Cynomolgus monkeys are outbred species and exhibit substantial levels of genetic variation which can affect the outcome and interpretation of biomedical studies. Copy number variations (CNVs) are a significant source of genetic diversity and a comprehensive understanding of the genomic impact of CNVs on phenotypic traits is limited. A custom 4.2 million probes comparative genomic hybridization (CGH) array (Design-ID: 120405_Cynomolgus5_CGH_UX1) has been designed on the basis of the Cynomolgus monkey genome (Ebeling et al. (2011) Genome Research; PMID: 21862625) to assess genome-wide copy number variation among Cynomolgus monkeys. Using Cynomolgus monkey specific NimbleGen CGH Microarrays we profiled the genomes of 21 Cynomolgus monkeys. Germline DNA from 21 Cynomolgus monkeys with different origin was tested against a Cynomolgus monkey reference. Cynomolus monkey samples were derived from breeding centers located in the Philippines (3 females and 3 males), in Vietnam (2 males and 2 females), in China for animals from Mainland Southeast Asia (3 females), or in Mauritius (4 females and 4 males). Furthermore genome-wide expression profiles were analyzed in 5 vitally important tissue samples (heart, kidney, liver, lung, spleen) from the same animals using a custom Cynomolgus monkey specific NimbleGen gene expression microarray (design ID: 120419_Cynomolgus_v5_TH_exp_HX12) to associate CNV genotypes with expression changes of proximal genes using a cis expression quantitative trait loci (cis-eQTL) mapping approach. Expression data have been deposited at the NCBI Gene Expression Omnibus (GEO) under accession numbers GSE76560. The array CGH results analyzed in this study are further described in Gschwind A.R. et al. (2016) "Diversity and regulatory impact of copy number variation in the primate Macaca fascicularis". under submission
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Project description:Non-human primates (NHP) are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types from the cynomolgus monkey Macaca fascicularis (denoted as ‘Monkey Atlas’) using both single-cell chromatin accessibility (scATAC-seq) and RNA sequencing (scRNA-seq) data at the organism-wide level. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type composition and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we inferred pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identified various cell-specific cis-regulatory elements and constructed organ-specific gene regulatory networks at the single-cell level. Finally, we performed a comparative analysis of single-cell landscapes among mouse, cynomolgus monkey and human, and we showed that cynomolgus monkey has significantly higher degree of cell-type similarity to human than mouse. Taken together, our study provides a valuable resource for NHP cell biology.
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Project description:MECP2-R270X transgenic mice (TG) and MECP2-G273X TG mice were generated in the Zoghbi Lab. These mice express the respective truncated form of MeCP2 tagged with GFP at the C-terminus from a transgenic human PAC containing all known regulatory sequences. These transgenes were maintained on a wild-type pure FVB background. For experiments each transgenic line was crossed by Mecp2 null mice (Mecp2 tm1.1Bird) on a pure 129SvEv background and the resulting male F1 hybrid progeny (FVB;129SvEv) that lacked endogenous MeCP2 expression but expressed either transgene (Mecp2 -/y; MECP2-R270X TG or Mecp2-/y; MECP2-G273X TG) were used for ChIP-Seq analysis. Whole brain from either the R270X mice (Mecp2 -/y; MECP2-R270X TG) or the G273X mice (Mecp2 -/y; MECP2-G273X TG) was formaldehyde crosslinked and purified chromatin was immunoprecipitated with anti-GFP antibody (Abcam ab6556). 2 samples: R270X (Mecp2 -/y; MECP2-R270X TG) and G273X (Mecp2 -/y; MECP2-G273X TG) both on an F1 (FVB;129SvEv) hybrid background
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Project description:MECP2-R270X transgenic mice (TG) and MECP2-G273X TG mice were generated in the Zoghbi Lab. These mice express the respective truncated form of MeCP2 tagged with GFP at the C-terminus from a transgenic human PAC containing all known regulatory sequences. These transgenes were maintained on a wild-type pure FVB background. For experiments each transgenic line was crossed by Mecp2 null mice (Mecp2 tm1.1Bird) on a pure 129SvEv background and the resulting male F1 hybrid progeny (FVB;129SvEv) that lacked endogenous MeCP2 expression but expressed either transgene (Mecp2 -/y; MECP2-R270X TG or Mecp2-/y; MECP2-G273X TG) were used for ChIP-Seq analysis. Whole brain from either the R270X mice (Mecp2 -/y; MECP2-R270X TG) or the G273X mice (Mecp2 -/y; MECP2-G273X TG) was formaldehyde crosslinked and purified chromatin was immunoprecipitated with anti-GFP antibody (Abcam ab6556).
2013-03-12 | GSE36536 | GEO