Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development
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ABSTRACT:
ORGANISM(S): Macaca mulatta
PROVIDER: GSE56962 | GEO | 2019/12/01
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.
2015-11-25 | E-GEOD-57974 | biostudies-arrayexpress
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.
2015-11-25 | GSE57974 | GEO
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:Type 2 diabetes mellitus (TM) is a severely metabolic disorder that affects above 10% worldwide population. Obesity is a major cause of insulin resistance and contributes to the development of TM. Liver is an essential metabolic organ that plays crucial roles in the pathogenesis of obesity and diabetes. However, the underlying mechanisms of liver in the transition of obesity to diabetes are not fully understood. Nonhuman primate (NHP) rhesus monkey is an appropriate animal for research of human diseases. Here, we first screened and selected three individual spontaneous and diabetic rhesus monkeys. Interestingly, the diabetic monkeys were obese with high BMI at beginning, but gradually lost their body weight during one-year observation. Furthermore, we performed a SILAC-based quantitative proteomics to identify proteins and signaling pathways with altered expression in the liver of obese and diabetic monkeys. Totally, 3509 proteins were identified and quantified, and of which 185 proteins displayed altered expression level. GO analysis revealed that the expression of proteins involved in fatty acids β-oxidation and galactose metabolism was increased in obese monkeys; while proteins involved in oxidative phosphorylation (OXPHOS) and branched chain amino acid (BCAA) degradation was upregulated in diabetic monkeys. In addition, we observed a mild impaired mitophagy and apoptosis in the liver of diabetic monkeys, suggesting a dysfunction of mitochondria and liver injury in the late onset of diabetics. Taken together, our liver proteomics may reveal a distinct metabolic transition from fatty acids β-oxidation in obese monkey to BCAA degradation in diabetic monkeys.
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Project description:The cerebral cortex is a pivotal structure that is integral to advanced brain functions within the mammalian central nervous system. Patterns of DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'- hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in early stages can profoundly alter the epigenetic regulation program, which provides new insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.
2022-10-31 | GSE215230 | GEO
Project description:The cerebral cortex is a pivotal structure that is integral to advanced brain functions within the mammalian central nervous system. Patterns of DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'- hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in early stages can profoundly alter the epigenetic regulation program, which provides new insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.
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Project description:The cerebral cortex is a pivotal structure that is integral to advanced brain functions within the mammalian central nervous system. Patterns of DNA methylation and hydroxymethylation play important roles in regulating cerebral cortex development. However, it remains unclear whether abnormal cerebral cortex development, such as microcephaly, could rescale the epigenetic landscape, potentially contributing to dysregulated gene expression during brain development. In this study, we characterize and compare the DNA methylome/hydroxymethylome and transcriptome profiles of the cerebral cortex across several developmental stages in wild-type (WT) mice and Mcph1 knockout (Mcph1-del) mice with severe microcephaly. Intriguingly, we discover a global reduction of 5'- hydroxymethylcytosine (5hmC) level, primarily in TET1-binding regions, in Mcph1-del mice compared to WT mice during juvenile and adult stages. Notably, genes exhibiting diminished 5hmC levels and concurrently decreased expression are essential for neurodevelopment and brain functions. Additionally, genes displaying a delayed accumulation of 5hmC in Mcph1-del mice are significantly associated with the establishment and maintenance of the nervous system during the adult stage. These findings reveal that aberrant cerebral cortex development in early stages can profoundly alter the epigenetic regulation program, which provides new insights into the molecular mechanisms underpinning diseases related to cerebral cortex development.
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Project description:Rhesus Monkey is one of the important primate models widely used in the fields of disease mechanism study, pre-clinical test in drug discovery and molecular evolution. However, the majority of rhesus gene annotations were putatively mapped from human genome, with only 10% supported by rhesus EST data.So, to better study the transcriptome, paired-end, strand-specific, poly(A)-positive RNA-Seq were performed in 5 rhesus monkey tissues. 5 tissue samples examined: prefrontal cortex, liver, skeletal muscle, adipose, testis
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