Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression data from postnatal cerebellum, prefrontal cortex and liver: comparison on tissue differences (miRNA)

ABSTRACT: To understand the roles of molecules in functional differentiation among adult human tissues, we performed a systematic survey of mRNA, protein, and protein phosphorylation as well as miRNA expression, in three tissues: cerebellum, prefrontal cortex and liver. We found that tissues were clearly distinct from one another at all levels. Furthermore, our results showed that miRNA differently expressed between tissues have significant, but modest effect on expression of mRNA and somewhat stronger effect on expression of proteins among the tissues. Notably, miRNA preferentially targeted gene regulators, transcription factors and kinases, in all three tissues studied. Following this path, we found that miRNA effect was further amplified through expression changes of target transcription factors and kinases, leading to further changes in their targets’ expression and phosphorylation levels. Importantly, miRNA regulation leads to reduced, rather than increased gene expression variation among individuals between two brain regions. These observations uncover the complexity of miRNA regulatory interactions and are compatible with suggested role of miRNA in gene expression canalization. Adult human post-mortem tissue samples: cerebellum, prefrontal cortex and liver, were collected. Each tissue contains three individuals totalling 9 samples in this datasets. RNA extracted from these dissected tissue was hybridized to Agilent Human miRNA Microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Ning Fu

PROVIDER: E-GEOD-19505 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Among other factors, changes in gene expression on the human evolutionary lineage have been suggested to play an important role in the establishment of human-specific phenotypes. However, the molecular mechanisms underlying these expression changes are largely unknown. Here, we have explored the role of microRNA (miRNA) in the regulation of gene expression divergence between adult humans, chimpanzees and rhesus macaques, in two brain regions: prefrontal cortex and cerebellum. Using combination of high-throughput sequencing, miRNA microarrays and Q-PCR, we have shown that up to 11% of the 325 expressed miRNA diverged significantly between humans and chimpanzees and up to 31% - between humans and macaques. Measuring mRNA and protein expression in human and chimpanzee brains, we found a significant inverse relationship between the miRNA and the target genes expression divergence, explaining 2-4% of mRNA and 4-6% of protein expression differences. Notably, miRNA showing human-specific expression localize in neurons and target genes that are involved in neural functions. Enrichment in neural functions, as well as miRNA-driven regulation on the human evolutionary lineage, were further confirmed by experimental validation of predicted miRNA targets in two neuroblastoma cell lines. Finally, we identified a signature of positive selection in the upstream region of one of the five miRNA with human-specific expression, miR-34c-5p. This suggests that miR-34c-5p expression change took place after the split of the human and the Neanderthal lineages and had adaptive significance. Taken together these results indicate that changes in miRNA expression might have contributed to evolution of human cognitive functions. Human, chimpanzee, and rhesus: mRNA, microRNA, and microRNA sequencing. Neuroblastoma cell lines: miRNA transfection experiments were conducted on two human-derived neuroblastoma cell lines (SH-SY5Y and SK-N-SH). Briefly, cells were plated in 0.5ml of growth medium, without antibiotics, 24h prior to transfection. miRNA mimics-Lipofectamine 2000 (Invitrogen) complexes were prepared freshly before transfection according to the manufacturer's protocol. SH-SY5Y and SK-N-SH cells were transfected in six-well plates using miRNA mimics-Lipofectamine 2000 with a final oligonucleotide concentration of 10nmol/L. In parallel, negative control transfections with mock oligonucleotides were conducted according to the manufacturer's protocol. For each cell line, transfections with negative control oligonucleotides were carried out in two independent replicates. Cells were harvested after 24h, total RNA were extracted with Trizol reagent (Invitrogen) and further processed and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays following the manufacturer's instructions. The gene expression levels were determined using rma in the R Affy package.

Project description:Caloric restriction (CR) can delay morbidity and mortality in a broad range of species, including mice and macaques. Mutations and chemical agents, such as resveratrol or rapamycin that partly mimic the CR effect, can similarly increase survival or extend lifespan. In humans, however, the effects of CR or other life-extending agents have not been investigated systematically. Humans already display lower mortality and greater maximal lifespan compared to closely related species, including chimpanzees and macaques. It is thus possible that humans, during their evolution, have acquired genetic mutations mimicking the CR effect. To address this question, we compared transcriptome differences between humans and other primates, with transcriptome changes observed in mice subjected to CR [see references below]. We show that the human transcriptome state examined in multiple tissues and across different ages resembles the transcriptome state of mice fed ad libitum, relative to CR mice or mice treated with resveratrol. Furthermore, transcriptome changes induced by CR were enriched among genes showing age-related changes among primates, concentrated in specific expression patterns, and could be linked with specific functional pathways, including insulin signalling, cancer, and immune response. These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may offer a promising direction in the extension of healthy human lifespan. References for the transcriptome changes observed in mice subjected to CR: 1) Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, et al: A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008, 3:e2264. 2) Tsuchiya T, Dhahbi JM, Cui X, Mote PL, Bartke A, Spindler SR: Additive regulation of hepatic gene expression by dwarfism and caloric restriction. Physiol Genomics 2004, 17:307-315. 3) Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al: Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006, 444:337-342. We collected post-mortem brain, heart, and liver samples from 16 human, 16 chimpanzee and 4 rhesus macaque seperately. All these individuals are adults. RNA extracted from the dissected tissue was hybridized to AffymetrixM-BM-. Human Gene 1.0 ST arrays to quantify gene expression level. We collected prefrontal cortex tissues of mice with age ranging from postnatal 2 days to 2.5 years. The strain of the mice is C57BL/6. RNA extracted from the dissected tissue was hybridized to AffymetrixM-BM-. Mouse Gene 1.0 ST Arrays to quantify gene expression level.

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Gene expression data from postnatal cerebellum, prefrontal cortex and liver: comparison on tissue differences (miRNA)

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