PXD038485

PXD038485 is an original dataset announced via ProteomeXchange.

Title	The LHX2-OTX2 regulatory module controls RPE differentiation and underlies a causal regulatory risk-SNP in age-related macular degeneration
Description	Tissue-specific transcription factors control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of transcription factors 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 transcription factors 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 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 SNP in the multifactorial common blinding disease AMD.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:43:56.912.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tamar Ziv
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-01 03:45:06	ID requested
1	2023-03-11 11:46:26	announced
⏵ 2	2023-11-14 08:43:58	announced	2023-11-14: Updated project metadata.

Cohen-Gulkar M, David A, Messika-Gold N, Eshel M, Ovadia S, Zuk-Bar N, Idelson M, Cohen-Tayar Y, Reubinoff B, Ziv T, Shamay M, Elkon R, Ashery-Padan R, The LHX2-OTX2 transcriptional regulatory module controls retinal pigmented epithelium differentiation and underlies genetic risk for age-related macular degeneration. PLoS Biol, 21(1):e3001924(2023) [pubmed]

submitter keyword: LDB1, retinal pigmented epithelium,: LHX2, cell-differentiation, OTX2, AMD, risk-SNP

Ruth Ashery-Padan
contact affiliation	Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel
contact email	ruthash@tauex.tau.ac.il
lab head
Tamar Ziv
contact affiliation	Technion
contact email	tamarz@technion.ac.il
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD038485

PRIDE project URI

• PRIDE
  1. PXD038485
     1. Label: PRIDE project
     2. Name: The LHX2-OTX2 regulatory module controls RPE differentiation and underlies a causal regulatory risk-SNP in age-related macular degeneration