July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
S100A4 deficiency-induced aberrant gene expression during lens differentiation is epigenetically regulated through altered Histone 3 lysine methylation marking
Author Affiliations & Notes
  • Rupalatha Maddala
    Ophyhalmology, Duke University Medical Center, Durham, North Carolina, United States
  • Susan K Murphy
    Division of Reproductive Sciences, Duke University Medical Center, Durham, North Carolina, United States
  • Vasanth Rao
    Ophthalmology, Pharmacology, Duke University Medical Center, Durham, North Carolina, United States
  • Footnotes
    Commercial Relationships   Rupalatha Maddala, None; Susan Murphy, None; Vasanth Rao, None
  • Footnotes
    Support  Nih Grants EY027053; EY25096
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3301. doi:
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      Rupalatha Maddala, Susan K Murphy, Vasanth Rao; S100A4 deficiency-induced aberrant gene expression during lens differentiation is epigenetically regulated through altered Histone 3 lysine methylation marking. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3301.

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

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Abstract

Purpose : To seek molecular insights into the effects of S100A4 deficiency on expression of photoreceptor and Muller glial cell-specific genes in differentiating mouse lens fibers.

Methods : Based on our observation that S100A4 deficiency is associated with aberrant gene expression and enrichment of genes with histone 3K methylation markings in mouse lenses, we evaluated changes in lysine trimethylation of histone 3K in P30 lenses using Epiquik Global Trimethyl Histone (H3K27 and H3K4) kits and immunohistochemical analyses. Changes in CpG island DNA methylation were evaluated by pyrosequencing selected genes.

Results : Deficiency of S100A4, a small molecular Ca2+ binding protein that exhibits a discrete expression profile during lens differentiation, leads to aberrant differentiation programs of retinal and olfactory neurons in mouse lens. RNA-seq based analysis of differential gene expression profiles revealed significant enrichment of genes with high and intermediate CpG-dense promoters bearing histone trimethylation of H3K27, H3K4 and bivalent H3K27 and H3K4. There were also changes in gene expression of DNA and histone methyltransferases and demethylases including Kdm5d, Kdm1a, Dnmt3a and Ktm2b, chromatin remodeling complex proteins (Smarcd1) and Polycomb repressive complex 2-associated protein (Epop) in S100A4-deficient lenses relative to littermate control lenses. S100A4 deficient lenses revealed a significant decrease and increase, respectively, in trimethylation of H3K27 and H3K4, as compared to control lenses. Additionally, CpG island DNA hypomethylation was noted for certain differentially upregulated genes in S100A4 null lenses relative to control lenses.

Conclusions : This study uncovers a crucial role for epigenetic regulation of gene expression through H3K27 and H3K4 trimethylation and DNA methylation during lens differentiation, and demonstrates that S100A4 deficiency-associated dysregulation of these processes leads to aberrant expression of photoreceptor, olfactory and Muller glia neuronal genes in lens fibers.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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