September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
FOXS1 drives EMT in retinal pigment, mammary and hepatic epithelial cells through p38 activation by TGFΒ1 and TNFa
Author Affiliations & Notes
  • Timothy A Blenkinsop
    Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Tomasz Swigut
    Stanford University, Stanford, California, United States
  • Nathan Boles
    Neural Stem Cell Institute, Albany, New York, United States
  • Rajini Srinivasan
    Stanford University, Stanford, California, United States
  • Qingjie Wang
    Neural Stem Cell Institute, Albany, New York, United States
  • Jeffrey Stern
    Neural Stem Cell Institute, Albany, New York, United States
  • Joanna Wysocka
    Stanford University, Stanford, California, United States
  • Sally Temple
    Neural Stem Cell Institute, Albany, New York, United States
  • Footnotes
    Commercial Relationships   Timothy Blenkinsop, None; Tomasz Swigut, None; Nathan Boles, None; Rajini Srinivasan, None; Qingjie Wang, None; Jeffrey Stern, None; Joanna Wysocka, None; Sally Temple, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5363. doi:
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      Timothy A Blenkinsop, Tomasz Swigut, Nathan Boles, Rajini Srinivasan, Qingjie Wang, Jeffrey Stern, Joanna Wysocka, Sally Temple; FOXS1 drives EMT in retinal pigment, mammary and hepatic epithelial cells through p38 activation by TGFΒ1 and TNFa. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5363.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To reveal novel factors in the development of Proliferative vitreoretinopathy by examining Retinal Pigment Epithelial (RPE) cells undergoing an Epithelial to Mesenchymal Transition (EMT). We tested the hypothesis that the combination of TGFb1 and TNFa induces a more severe transition in RPE towards acquiring mesenchymal properties, which are two factors RPE are exposed to during rhegmatogenous retinal detachment.

Methods : Using cultured adult human RPE we compared the effect of TGFb1 and/or TNFa on inducing EMT in RPE. RPE were cultured in the presence or absence of TGFb1 and/or TNFa. Human globes from donors varied from 51-89 years of age. All experiments conducted using human RPE from at least three individual donors. Comparison of relative gene expression was analyzed using a cutoff of 2-fold expression change for identifying differentially expressed genes.

Results : We found that TGFb1 and TNFa pathways synergistically activate an EMT program in adult human RPE, resulting in manifestations similar to those observed in PVR. To characterize the molecular mechanism underlying this cellular transition we mapped epigenomic and transcriptional changes and identified a set of transcription factors that are upregulated upon EMT induction in the adult RPE. Among those, we found that FOXS1, while not expressed in normal RPE, is highly induced in response to TGFb1 and TNFa in combination. In turn, FOXS1 is necessary and sufficient for SNAIL and SLUG expression, two master EMT transcription factors. Furthermore, consistent with a more general role in promoting EMT in various biological contexts, FOXS1 also drives EMT in human mammary and hepatic epithelial cells, and has increased copy numbers in a large number of metastatic cancers.

Conclusions : Using an unbiased transcriptomic and epigenetic approach, we identify FOXS1 to be a key regulator in EMT generally, and more specifically, we found FoxS1 may play a role in RPE driven PVR

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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