title: LSD1-Mediated Demethylation of H3K4me2 Is Required for the Transition from Late Progenitor to Differentiated Mouse Rod Photoreceptor.
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.
authors: Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
authors: Evgenya Y
authors: EY
authors: Popova
authors: Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
authors: Carolina
authors: C
authors: Pinzon-Guzman
authors: Bioinformatics Core, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA.
authors: Anna C
authors: AC
authors: Salzberg
authors: Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. ssz3@psu.edu.|Henan Eye Institute, 7 Weiwu Road, Zhengzhou, Henan, 450007, China. ssz3@psu.edu.
authors: Samuel Shao-Min
authors: SS
authors: Zhang
authors: Department of Neural and Behavioral Sciences, Penn State University College of Medicine, 500 University Drive, Hershey, PA, 17033, USA. cbarnstable@psu.edu.
authors: Colin J
authors: CJ
authors: Barnstable
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D000073398:Demethylation; D053263:Gene Regulatory Networks / Q000502:physiology; D056466:Histone Demethylases / Q000096:biosynthesis*; D006657:Histones / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D009924:Organ Culture Techniques; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*
chemical_list: D006657:Histones; D056466:Histone Demethylases; C504076:KDM1a protein, mouse
keywords: Epigenetics; H3K4me2; Histone demethylation; LSD1; Retina development; Rod photoreceptor