Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model.
Aged
Animals
Chromatin
/ genetics
Disease Models, Animal
Epigenesis, Genetic
/ genetics
Histone Deacetylases
/ drug effects
Histone-Lysine N-Methyltransferase
/ antagonists & inhibitors
Humans
Macular Degeneration
/ drug therapy
Mice
Photoreceptor Cells, Vertebrate
/ metabolism
Photosensitivity Disorders
/ genetics
Retina
/ metabolism
Retinal Degeneration
/ drug therapy
Retinal Pigment Epithelium
/ metabolism
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
29 08 2020
29 08 2020
Historique:
received:
02
05
2020
revised:
11
07
2020
accepted:
15
07
2020
pubmed:
22
7
2020
medline:
31
8
2021
entrez:
22
7
2020
Statut:
ppublish
Résumé
Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling was accomplished by employing an Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq), which revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Of particular interest, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3-9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby elucidating a potential new therapeutic strategy to combat AMD.
Identifiants
pubmed: 32691052
pii: 5874042
doi: 10.1093/hmg/ddaa158
pmc: PMC7471509
doi:
Substances chimiques
Chromatin
0
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Suv39h2 protein, mouse
EC 2.1.1.43
Hdac11 protein, mouse
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2611-2624Subventions
Organisme : NEI NIH HHS
ID : R01 EY009339
Pays : United States
Organisme : NEI NIH HHS
ID : U01 EY025451
Pays : United States
Organisme : BLRD VA
ID : IK2 BX002683
Pays : United States
Organisme : NEI NIH HHS
ID : R24 EY027283
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007250
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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