title: Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.
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.
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN, 38163, USA, echaum@uthsc.edu.
authors.forename: Edward
authors.initials: E
authors.lastname: Chaum
authors.forename: Christina S
authors.initials: CS
authors.lastname: Winborn
authors.forename: Sujoy
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053471:Caspases, Initiator; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D061251:Primary Cell Culture; D040641:Quantitative Trait Loci; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C554331:Ifna2 protein, mouse; D016898:Interferon-alpha; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator