Engineered regulatory states resolve context-dependent genetics in macular degeneration
- 1Memorial Sloan Kettering Cancer Center
Abstract
The effects of many genes and disease-associated variants remain hidden in standard cellular models, limiting functional interpretation. Here we engineer regulatory states via CRISPR activation of transcription factors (TFs) in human RPE-1 cells, a model for age-related macular degeneration (AMD). Multiome Perturb-seq profiling of single-TF perturbations identified regulators that selectively opened chromatin at AMD GWAS variants inaccessible in resting RPE-1. Priming of partner motifs in chromatin made accessible by single-TF perturbations predicted TF pairs generating emergent transcriptional states in combinatorial Perturb-seq, providing a design principle for selecting informative interactions. Distinct TF pairs also showed variable convergence between polygenic AMD signals and Mendelian retinal disease genes, supporting an omnigenic model shaped by regulatory states. Finally, Mosaic, a chromatin-informed model of TF interaction phenotypes, nominated out-of-sample regulators, including a higher-order combination with experimentally validated emergent effects on AMD-associated programs. Engineered regulatory states thus bring hidden disease biology within experimental reach.
Related
- Distinct regulatory networks mediate plant adaptation to multifactorial abiotic stress combinations: rethinking of plant stress genetics
- Systems genetics identifies ETS1 as a stress-dependent regulator of adipocyte insulin action and heme-iron homeostasis
- CD19 CAR Engineered T Regulatory Cells Promote Durable Immune Tolerance in Experimental Systemic Lupus Erythematosus
- Structural basis for the CsrA-dependent modulation of translation initiation by an ancient regulatory protein.
- Hierarchical Regulatory Module AcERF1-AcHAT5-AcERF10 Modulates Ethylene-Dependent Starch Degradation in Postharvest Kiwifruit.
BibTeX
@misc{metzner2026engineered,
title = {{Engineered regulatory states resolve context-dependent genetics in macular degeneration}},
author = {E. Metzner and K. Guruvayurappan and K. M. Southard and R. C. Ardy and K. K. Dey and T. M. Norman},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.758047},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.758047v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Engineered regulatory states resolve context-dependent genetics in macular degeneration
AU - E. Metzner
AU - K. Guruvayurappan
AU - K. M. Southard
AU - R. C. Ardy
AU - K. K. Dey
AU - T. M. Norman
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.758047
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.758047v1
AB - The effects of many genes and disease-associated variants remain hidden in standard cellular models, limiting functional interpretation. Here we engineer regulatory states via CRISPR activation of transcription factors (TFs) in human RPE-1 cells, a model for age-related macular degeneration (AMD). Multiome Perturb-seq profiling of single-TF perturbations identified regulators that selectively opened chromatin at AMD GWAS variants inaccessible in resting RPE-1. Priming of partner motifs in chromatin made accessible by single-TF perturbations predicted TF pairs generating emergent transcriptional states in combinatorial Perturb-seq, providing a design principle for selecting informative interactions. Distinct TF pairs also showed variable convergence between polygenic AMD signals and Mendelian retinal disease genes, supporting an omnigenic model shaped by regulatory states. Finally, Mosaic, a chromatin-informed model of TF interaction phenotypes, nominated out-of-sample regulators, including a higher-order combination with experimentally validated emergent effects on AMD-associated programs. Engineered regulatory states thus bring hidden disease biology within experimental reach.
ER -