Postnatal onset of retinal degeneration by loss of embryonic Ezh2 repression of Six1.
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.
Department of Ophthalmology and Ophthalmic Laboratories, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.|Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Naihong
N
Yan
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.|State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 54 South Xianlie Road, Guangzhou, Guangdong, P. R. China.
Lin
L
Cheng
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Kinsang
K
Cho
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Muhammad Taimur A
MT
Malik
Department of Ophthalmology and Ophthalmic Laboratories, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.
Lirong
L
Xiao
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Chenying
C
Guo
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Honghua
H
Yu
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
Ruilin
R
Zhu
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.|Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, Comprehensive Cancer Center, Department of Pathology, University of Michigan Ann Arbor, Michigan, USA.|Division of Ophthalmology, Surgical Service, Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan, USA.
Rajesh C
RC
Rao
Schepens Eye Research Institute, Massachusetts Eye &Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.|Veterans Administration Boston Healthcare System, Boston, Massachusetts, USA.
Dong Feng
DF
Chen
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