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MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

ABSTRACT: Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.

SUBMITTER: Somel M

PROVIDER: S-EPMC2928499 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

Somel Mehmet M Guo Song S Fu Ning N Yan Zheng Z Hu Hai Yang HY Xu Ying Y Yuan Yuan Y Ning Zhibin Z Hu Yuhui Y Menzel Corinna C Hu Hao H Lachmann Michael M Zeng Rong R Chen Wei W Khaitovich Philipp P

Genome research 20100720 9

Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few ge ...[more]

PMID: 20647238

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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.

Dataset Information

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

Publications

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

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