In PLOS Biology, researchers from Tel Aviv University and other centers in Israel report on findings from a tissue-specific transcription factor-based approach for untangling regulatory shifts behind adult-onset macular degeneration (AMD), an eye condition that affects the retinal pigmented epithelium (RPE). With RNA sequencing, chromatin immunoprecipitation sequencing, and other analyses of human embryonic stem cell-derived RPE cells, the team focused in on a regulatory module that includes the LHX2 and OTX2 transcription factors — a regulatory region that was subsequently linked to TRPM1 expression and to a known AMD-associated locus through expression quantitative trait locus, ATAC-seq, and reporter assay analyses. "Through functional and genomic analyses, we reveal that LHX2 functions upstream and together with OTX2 on shared genomic regions (cistrome) in regulation of target genes," the authors report, adding that "intersecting the map of the LHX2-OTX2 bound cistrome with published genomic data on AMD revealed a causal non-coding risk SNP that acts by altering TRPM1 expression in the RPE through the modulation of LHX2 binding to its promoter."