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, Cohen-Gulkar et al. 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. They show 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. Crucially, they also reveal a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE by modulating LHX2 transcriptional activity at 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 variant in the multifactorial common blinding disease AMD. The image shows a composite of an embryonic mouse eye cup (at stage E14.5) labeled with antibodies against the developmental transcription factors Lhx2 (red) and Otx2 (green), and cultured human retinal pigmented epithelium (RPE) labeled with antibodies against MITF (red) and ZO-1 (green).

Image Credit: Mazal Cohen-Gulkar and Ruth Ashery-Padan