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Phillip E Kish, Christina Tingle, Brian Magnuson, Curtis Heisel, Alon Kahana; Epigenetic regulation of myocyte dedifferentiation and myofiber growth during zebrafish EOM regeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2172.
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© ARVO (1962-2015); The Authors (2016-present)
Regeneration of adult zebrafish extraocular muscles (EOM) via dedifferentiation requires transcriptional reprogramming of injured myocytes, as revealed via transcriptome analysis (1,2). This process begins with down-regulated expression of genes that confer muscle identity, significant changes in metabolic programs, coordinated activation of protein degradation, and the synthesis of new proteins, including important alterations in transcription factor expression. We hypothesize that epigenetic regulation of transcription is required to drive the broad programmatic genomic changes required for myocyte dedifferentiation.1. Saera-Vila, A., et al., Invest Ophthalmol Vis Sci, 2015. 56(8): p. 4977-93.2. Louie et al., BMC Genomics, 2017. 18:854.
Following a 50% myectomy of the lateral rectus muscle, the reprogramming extant myocytes were collected at 0, 9 and 18 hours post injury (hpi) and processed for ChIP-Seq using published methods with antibodies against H3K27-Ac, H3K27-Me3 and H3K4-Me3. WebGestalt and over-representation analysis (ORA) were used to compare active regions identified by ChIP-Seq and RNA-Seq. ORA identifies whether a pre-filtered gene list was significantly associated with a particular pathway(s). This analysis included lists filtered using defined parameters to select for a minimum 1.25 fold change in representation of modification in either direction.
ORA identified genes with increasing or decreasing enrichment of acetylation or tri-methylation in active regions within the gene and promoter region. Analyses run with these parameters show enrichment with decreasing H3K27-Ac, increasing H3K27-Me3, and both increasing and decreasing H3K4-Me3.
We propose a mechanistic overview of the temporal orchestration of pathways involved in cellular reprogramming of injured EOMs. We also assess the importance of early-activated chromatin remodeling factors (Ezh2 and Suz12a) during the dedifferentiation and cell cycle reentry of “post-mitotic” EOM myocytes. Understanding the mechanisms involved in EOM regeneration in zebrafish may improve treatment of human strabismic conditions.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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