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Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium

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Abstract

The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFNα in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset (www.genenetwork.org) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172–177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.

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Acknowledgments

These studies were supported in part by an unrestricted UTHSC departmental grant from Research to Prevent Blindness, New York, NY, the Plough Foundation, Memphis, TN, The Lions of Arkansas Foundation Inc., and the UTHSC Hamilton Eye Institute NEI Core Grant for Vision Research (P30 EY013080). The authors would also like to thank Dr. Rob Williams for his comments and review of the manuscript.

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Authors and Affiliations

  1. Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Edward Chaum, Christina S. Winborn & Sujoy Bhattacharya

  2. Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Edward Chaum

  3. Hamilton Eye Institute, 930 Madison Ave. Suite 731, Memphis, TN, 38163, USA

    Edward Chaum

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  1. Edward Chaum
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  2. Christina S. Winborn
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  3. Sujoy Bhattacharya
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Correspondence to Edward Chaum.

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335_2015_9568_MOESM1_ESM.tif

Fig. S1. Expression of Cdkn1a, Cdkn2a and Cdkn2b in the retina of BXD mice. Data illustrates variable expression in BXD mouse retinas for (A) Cdkn1a, (B) Cdkn2a and (C) Cdkn2b. Mean expression and range (expression fold change) for Cdkn1a, Cdkn2a and Cdkn2b are 7.86 (±3.32), 7.19 (±1.6) and 7.29 (±2.65), respectively. Supplementary material 1 (TIFF 8997 kb)

335_2015_9568_MOESM2_ESM.tif

Fig. S2. Expression of candidate genes in the Qrr1 locus in the retina of BXD mice. Data illustrates varied expression of (A) Fcer1γ, (B) Fcgr3, (C) Fmn2 and (D) Ifi205 in BXD mice retinas. Mean expression and rage (fold) for these candidate genes are 7.64 (±6.28), 7.31 (±2.44), 9.18 (±2.91) and 6.811 (±2.19), respectively. Supplementary material 2 (TIFF 8305 kb)

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Chaum, E., Winborn, C.S. & Bhattacharya, S. Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium. Mamm Genome 26, 210–221 (2015). https://doi.org/10.1007/s00335-015-9568-9

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  • DOI: https://doi.org/10.1007/s00335-015-9568-9

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