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Lu Lu, Jessica Baker, Eldon E Geisert, Wenbo Zhang; Analysis of Sirt6 molecular networks in mouse retina. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2725. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The mammalian sirtuin 6 (Sirt6) is a nuclear, chromatin-bound protein which functions as a nicotinamide adenine dinucleotide (NAD)-dependent histone H3 lysine 9 (H3K9) and H3K56 deacetylase and represses the transcription activities of several transcription factors involved in aging, glucose metabolism and inflammation. Mice deficient in Sirt6 exhibit severe metabolic defects, premature aging phenotype and most of them die at about 4 weeks of age. Those survivors develop massive inflammation in several organs. Sirt6 is highly expressed in the retina, and mice deficient in Sirt6 exhibit retinal neuronal dysfunction and cell death, suggesting Sirt6 has an important role in normal retinal function and is potentially involved in retinal degenerative diseases such as diabetic retinopathy and glaucoma. Molecules that regulate Sirt6 expression in retina are unknown. The present study is to evaluate the upstream regulation of Sirt6, its genetic network of related genes and assessed its potential functions in retina development using genetic and bioinformatics methods.
Total RNA of retina was extracted from a cohort of 55 BXD strains and both C57BL/6J and DBA/2J parental. Expression was estimated using the Affymetrix Mouse Gene 2.0 ST array. Genetic mapping and bioinformatics analysis were conducted using tools in GeneNetwork.org and other linked web resources.
Expression of Sirt6 varies 1.37-fold among 55 BXD strains and expression level is relatively high (10.60± 0.11 SE log2 units). Expression of Sirt6 is not correlated with iris or coat color pigmentation but is correlated strongly with 52 other transcripts all of which share a common QTL on chromosome 11 at ~108 Mb (LRS scores of up to 28). The Cep112 gene was identified as the best candidate to modulate expression of this group of genes including Sirt6. Pathway analysis using KEGG highlights possible enrichment in the spliceosome network, mRNA surveillance, and RNA transport. Gene Ontology analysis or gene function analysis showed those genes are involved in histone activity and RNA process.
Sirt6 and 52 other genes are located in the same molecular network and Cep112 gene is identified as a common upstream gene that regulates the expression of these genes.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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