Abstract
Some adult-onset disorders may be linked to dysregulated embryonic development, yet the mechanisms underlying this association remain poorly understood. Congenital retinal degenerative diseases are blinding disorders characterized by postnatal degeneration of photoreceptors, and affect nearly 2 million individuals worldwide, but ∼50% do not have a known mutation, implicating contributions of epigenetic factors. We found that embryonic deletion of the histone methyltransferase (HMT) Ezh2 from all retinal progenitors resulted in progressive photoreceptor degeneration throughout postnatal life, via derepression of fetal expression of Six1 and its targets. Forced expression of Six1 in the postnatal retina was sufficient to induce photoreceptor degeneration. Ezh2, although enriched in the embryonic retina, was not present in the mature retina; these data reveal an Ezh2-mediated feed-forward pathway that is required for maintaining photoreceptor homeostasis in the adult and suggest novel targets for retinal degeneration therapy.
Highlights
Postnatal degeneration of photoreceptors underlies the most common causes of irreversible blindness
Inhibition of repressive histone methyltransferase (HMT) activity could lead to postnatal retinal degeneration through “developmental reprogramming” that stems from aberrant derepression of a subset of normally silenced genes[6]
Previous reports have shown that enhancer of zeste homolog 2 (Ezh2)/EZH2 is abundant during embryonic development but is absent during the late postnatal period and adulthood in mice and humans[9,10,11]
Summary
Postnatal degeneration of photoreceptors underlies the most common causes of irreversible blindness. Epigenetic events mediated by repressive histone methylation regulate the transcriptional programs in proliferating embryonic stem cells and their differentiated, post-mitotic progeny by suppressing transcription in specific fetal genes These early developmental events may serve as a nexus point of cell proliferation and differentiation that persists into adulthood to allow establishment of stabilized expression of postnatal genes and maintain tissue homeostasis. Perturbation of this process, via inhibition of repressive histone methyltransferase (HMT) activity in embryonic retinal progenitors, may lead to disruption of postnatal homeostasis. These findings provide new insights into how dysregulation of Ezh[2] function in development may contribute to retinal degeneration in postnatal life
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