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Evgenya Popova, Carolina Pinzon-Guzman, Anna Salzberg, Daniel Hass, Samuel Shao-Min Zhang, Colin J Barnstable; The role of Lysine demethylase 1 in mouse rod photoreceptor development and maturation.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):438.
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© ARVO (1962-2015); The Authors (2016-present)
The transition of dividing progenitors into terminally differentiated cells in the Central Nervous System requires large-scale repression of progenitor genes and activation of genes characteristic of each differentiated cell type. A key element in this reprogramming is the action of histone modifying enzymes inside complexes binding to promoters and enhancers of the genes. One of the well-characterized enzymes is lysine-specific demethylase 1(LSD1). LSD1 demethylates mono- and dimethylated H3K4 and H3K9. The purpose of this study was to understand how LSD1 may be involved in regulating the epigenetic status of genes during retina development and the role of this status in controlling rod photoreceptor maturation.
We compared pharmacological inhibition and conditional knockouts of this enzyme in developing mouse retina. Animal use was in accordance with ARVO/IACUC guidelines. Whole retina explants were isolated from C57BL/6j mice pups at postnatal day 1 and were cultured individually in media as a control or with LSD1inhibitors for 24h, 4 days or 8 days. Illumina MouseRef8 v2.0 Expression BeadChip (BD-202-0202) was processed starting with 500ng of template and using standard Illumina Total Prep protocol.
LSD1 is expressed in retinal postmitotic cells at the peak of rod photoreceptor differentiation. Pharmacological inhibition of LSD1 in retinal explants cultured from PN1 to PN8 had three major effects. It prevented normal decrease in expression of transcriptional repressors and genes associated with proliferation and progenitor specification; it blocked rod photoreceptor development and it increased expression of genes associated with other retinal cell types, including cone photoreceptors. We generated two Cre-loxP-mediated conditional knockout mice. Mice with LSD1 floxed alles (LSD1fl/fl) were crossed with Crx-Cre or Rho-Cre mice to create LSD1 knockouts in retina at two developing windows to determine LSD1 role in photoreceptor development and maturation. The results of this genetic approach will be compared with the pharmacological studies.
Our results indicate that LSD1 activity is essential both for the cessation of progenitor programs and for the correct execution of terminal differentiation programs.
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