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Clayton Santiago, John Ash; Epigenetic regulation of stress-induced LIF expression.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4395.
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© ARVO (1962-2015); The Authors (2016-present)
Stressed photoreceptors release signals that stimulate Müller glial cells to induce the expression of trophic factors. Leukemia Inhibitory Factor (LIF) is one of these critical factors. It has been demonstrated that LIF can delay the degeneration of injured photoreceptors by activating cell survival pathways. Prior to cell death, an increase in LIF expression is observed in mouse models of inherited retinal degeneration. Over time, this expression decreases, which accelerates photoreceptor cell death. Understanding the mechanism by which LIF expression is regulated is key to elucidating the factors that control the rate of retinal degeneration. The aim of this study is to identify elements that are required for the induction of LIF under stress.
All procedures with animals were conducted in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. BALB/cJ mice were exposed to light damage (LD) for 4 hours to induce LIF expression. Retinas were fixed, sonicated and prepared for chromatin immunoprecipitation (ChIP). The antibodies against RNA polII pS2, H3K4me, H3K4me3, H3K27ac or IgG were used. DNA was purified using a QIAquick extraction kit and analyzed by qPCR.
Upon light damage there is an increase of RNA Pol II occupancy within the gene body of LIF. Histone marks denoting enhancer elements (H3K4me and H3K27ac) are found predominately in the beginning of the LIF gene and within the first intron. The light damaged mice exhibit increased H3k4me3 levels within the second transcription start site of the LIF gene.
Our data suggests that increased transcription rates play a significant role in increasing steady state levels of LIF in a stressed retina. The majority of LIF mRNA may be transcribed from the alternative LIF promoter. H3K27ac and H3K4me levels identify potential enhancer elements within the first intron of the LIF gene body.
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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