Mapping convergent regulators of melanoma drug resistance by PerturbFate.

Publication Type	Academic Article
Authors	Xu Z, Lu Z, Ugurbil A, Abdulraouf A, Liao A, Zhang J, Zhou W, Cao J
Journal	Nature
Volume	654
Issue	8117
Pagination	261-271
Date Published	04/15/2026
ISSN	1476-4687
Keywords	Drug Resistance, Neoplasm, Melanoma, Single-Cell Gene Expression Analysis, Vemurafenib
Abstract	High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.
DOI	10.1038/s41586-026-10367-0
PubMed ID	41986722
PubMed Central ID	PMC13233327