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LSD1-Mediated Demethylation of H3K4me2 Is Required for the Transition from Late Progenitor to Differentiated Mouse Rod Photoreceptor

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Abstract

Epigenetic modifiers can work in concert with transcription factors to control the transition of cells from proliferating progenitors into quiescent terminally differentiated cells. This transition involves changes in histone methylation and one of the key regulators of this is the H3K4me2/1 histone demethylase LSD1. Here, we show that the highest expression of LSD1 occurs in postmitotic retinal cells during the peak period of rod photoreceptor differentiation. Pharmacological inhibition of LSD1 in retinal explants cultured from PN1 to PN8 had three major effects. It prevented the normal decrease in expression of genes associated with progenitor function, it blocked rod photoreceptor development, and it increased expression of genes associated with other retinal cell types. The maintained expression of progenitor genes was associated with a maintained level of H3K4me2 over the gene and its promoter. Among the genes whose expression was maintained was Hes1, a repressor known to block rod photoreceptor development. The inhibition of rod photoreceptor gene expression occurred in spite of the normal expression of transcription factors CRX and NRL, and the normal accumulation of H3K4me2 marks over the promoter and gene body. We suggest that LSD1 acts in concert with a series of nuclear receptors to modify chromatin structure and repress progenitor genes as well as to inhibit ectopic patterns of gene expression in the differentiating postmitotic retinal cells.

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Acknowledgments

This research was supported by NEI/NIH grant EY013865 and Macula Vision Research Foundation. We thank Rob Brucklacher from Penn State Hershey Genome Sciences Facility for help with gene expression microarray.

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    Authors and Affiliations

    1. Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

      Evgenya Y. Popova, Carolina Pinzon-Guzman, Samuel Shao-Min Zhang & Colin J. Barnstable

    2. Bioinformatics Core, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA

      Anna C. Salzberg

    3. Henan Eye Institute, 7 Weiwu Road, Zhengzhou, Henan, 450007, China

      Samuel Shao-Min Zhang

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    1. Evgenya Y. Popova
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    2. Carolina Pinzon-Guzman
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    3. Anna C. Salzberg
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    4. Samuel Shao-Min Zhang
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    Correspondence to Samuel Shao-Min Zhang or Colin J. Barnstable.

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    1. LSD1 is expressed at transition from late progenitors to rod photoreceptors

    2. Under LSD1 inhibition level of H3K4me2 maintained over the progenitor genes

    3. LSD1 inhibition prevented the normal decrease in expression of progenitor genes

    4. LSD1 inhibition blocked rod photoreceptor development

    5. LSD1 inhibition increased other retinal cell type’s genes expression

    Evgenya Y. Popova and Carolina Pinzon-Guzman contributed equally to this work.

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    Popova, E.Y., Pinzon-Guzman, C., Salzberg, A.C. et al. LSD1-Mediated Demethylation of H3K4me2 Is Required for the Transition from Late Progenitor to Differentiated Mouse Rod Photoreceptor. Mol Neurobiol 53, 4563–4581 (2016). https://doi.org/10.1007/s12035-015-9395-8

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    • DOI: https://doi.org/10.1007/s12035-015-9395-8

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