The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration.
Humans
Mice
Animals
LIM-Homeodomain Proteins
/ genetics
Genome-Wide Association Study
Proteomics
Macular Degeneration
/ genetics
Cell Differentiation
Epithelium
/ metabolism
Transcription Factors
/ genetics
TRPM Cation Channels
/ genetics
Otx Transcription Factors
/ genetics
DNA-Binding Proteins
/ metabolism
LIM Domain Proteins
/ genetics
Journal
PLoS biology
ISSN: 1545-7885
Titre abrégé: PLoS Biol
Pays: United States
ID NLM: 101183755
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
15
04
2022
accepted:
16
11
2022
entrez:
17
1
2023
pubmed:
18
1
2023
medline:
20
1
2023
Statut:
epublish
Résumé
Tissue-specific transcription factors (TFs) control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of TFs that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here, we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental TFs LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD genome-wide association study (GWAS) data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk single-nucleotide polymorphism (SNP) in the multifactorial common blinding disease AMD.
Identifiants
pubmed: 36649236
doi: 10.1371/journal.pbio.3001924
pii: PBIOLOGY-D-22-00876
pmc: PMC9844853
doi:
Substances chimiques
LIM-Homeodomain Proteins
0
LHX2 protein, human
0
Transcription Factors
0
TRPM1 protein, human
0
TRPM Cation Channels
0
OTX2 protein, human
0
Otx Transcription Factors
0
Ldb1 protein, mouse
0
DNA-Binding Proteins
0
LIM Domain Proteins
0
Lhx2 protein, mouse
0
Otx2 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e3001924Informations de copyright
Copyright: © 2023 Cohen-Gulkar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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