June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Epigenetic programming regulates lens fiber cell gene expression to achieve lens fiber cell form and function and is dependent on the hypoxic environment of differentiating lens fiber cells.
Author Affiliations & Notes
  • Lisa A Brennan
    Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States
  • Joshua Disatham
    Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States
  • Marc Kantorow
    Biomedical Science, Florida Atlantic University, Boca Raton, Florida, United States
  • Footnotes
    Commercial Relationships   Lisa Brennan None; Joshua Disatham None; Marc Kantorow None
  • Footnotes
    Support  NIH grant EY029708 (MK)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 4395. doi:
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      Lisa A Brennan, Joshua Disatham, Marc Kantorow; Epigenetic programming regulates lens fiber cell gene expression to achieve lens fiber cell form and function and is dependent on the hypoxic environment of differentiating lens fiber cells.. Invest. Ophthalmol. Vis. Sci. 2023;64(8):4395.

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

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Abstract

Purpose : We have demonstrated that activation and silencing of critical lens genes is governed by genome-wide regulation of chromatin accessibility. These studies show that differentiation-state specific re-positioning of nucleosomes and DNA methylation are key elements of gene regulation. DNA accessibility is also regulated by modification of histones by histone acetylases and lysine methytransferases. We have shown that the hypoxic environment of lens fiber cells drives key events required for lens fiber cell differentiation through activation of the master regulator of the hypoxic response, transcription factor HIF1a. HIF1a activity is regulated by access to DNA regulatory elements. Here, we test the hypothesis that hypoxia further controls lens fiber cell gene expression through regulation of key histone modifications that mediate chromatin accessibility and transcription factor access.

Methods : Using ex-vivo embryonic chick lens (E13) cultures we examined global histone modifications following exposure of lenses to hypoxia (1% O2). We used CUT & RUN to map the specific location of key histone modifications associated with gene activation (H3K4me3, H3K27ac) under hypoxic conditions. Using a multiomics approach we integrated CUT n RUN, and RNAseq data, to examine hypoxia regulation of key histones to drive the expression of key lens fiber cell genes.

Results : Western blot analysis of lens fibers extracted histones demonstrated a rapid and robust increase in multiple histone modifications that are associated with open chromatin and gene expression activation including H3K4me3, H3K27ac, H3K14ac and H3K9ac. CUT and RUN analysis of lens fiber cells following exposure to hypoxia identified increased H3K4 methylation and increased H3K27 acetylation in the promotor region of a number of critical lens fiber genes including BFSP1, BFSP2, TDRD7, BNIP3L, BIRC7 and EPHA2. These changes correlated with chromatin decondensation assessed by ATAC sequencing.

Conclusions : Collectively, these results provide evidence that epigenetic programming drives lens fiber cell gene expression to achieve mature lens structure and transparency and that the lens epigenetic landscape is dependent on the hypoxic environment of nascent lens fiber cells.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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