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Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.

ABSTRACT: Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf(-/-) blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf(+/-) mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH). To pursue the mechanism of impaired liver regeneration we examined activation of interleukin-6 (IL-6) a key cytokine required for induction of hepatocyte proliferation following PH. Peak induction of hepatic IL-6 mRNA abundance post PH was attenuated >80% in heterozygous Acf(+/-) mice, along with decreased serum IL-6 levels. IL-6 secretion from isolated Kupffer cells (KC) was 2-fold greater in wild-type compared with heterozygous Acf(+/-) mice. Recombinant ACF bound an AU-rich region in the IL-6 3'-untranslated region with high affinity and IL-6 mRNA half-life was significantly shorter in KC isolated from Acf(+/-) mice compared with wild-type controls. These findings suggest that ACF regulates liver regeneration following PH at least in part by controlling the stability of IL-6 mRNA. The results further suggest a new RNA target and an unanticipated physiological function for ACF beyond apoB RNA editing.

SUBMITTER: Blanc V

PROVIDER: S-EPMC2885197 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.

Blanc Valerie V Sessa Kimberly J KJ Kennedy Susan S Luo Jianyang J Davidson Nicholas O NO

The Journal of biological chemistry 20100420 25

Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf(-/-) blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf(+/-) mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH ...[more]

PMID: 20406809

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Project description:BackgroundDNA methylation in the 5' promoter regions of genes and microRNA (miRNA) regulation at the 3' untranslated regions (UTRs) are two major epigenetic regulation mechanisms in most eukaryotes. Both DNA methylation and miRNA regulation can suppress gene expression and their corresponding protein product; thus, they play critical roles in cellular processes. Although there have been numerous investigations of gene regulation by methylation changes and miRNAs, there is no systematic genome-wide examination of their coordinated effects in any organism.ResultsIn this study, we investigated the relationship between promoter methylation at the transcription level and miRNA regulation at the post-transcription level by taking advantage of recently released human methylome data and high quality miRNA and other gene annotation data. We found methylation level in the promoter regions and expression level was negatively correlated. Then, we showed that miRNAs tended to target the genes with a low DNA methylation level in their promoter regions. We further demonstrated that this observed pattern was not attributed to the gene expression level, expression broadness, or the number of transcription factor binding sites. Interestingly, we found miRNA target sites were significantly enriched in the genes located in differentially methylated regions or partially methylated domains. Finally, we explored the features of DNA methylation and miRNA regulation in cancer genes and found cancer genes tended to have low methylation level and more miRNA target sites.ConclusionThis is the first genome-wide investigation of the combined regulation of gene expression. Our results supported a complementary regulation between DNA methylation (transcriptional level) and miRNA function (post-transcriptional level) in the human genome. The results were helpful for our understanding of the evolutionary forces towards organisms' complexity beyond traditional sequence level investigation.

Dataset Information

Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.

Publications

Apobec-1 complementation factor modulates liver regeneration by post-transcriptional regulation of interleukin-6 mRNA stability.

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