The paper introduces PerturbFate, a highly scalable and cost-effective single-cell platform designed to map the complex regulatory programs that drive disease phenotypes. By integrating combinatorial indexing with CRISPR interference, the method simultaneously captures chromatin accessibility, nascent transcription, and mature mRNA from individual cells. The authors demonstrate its utility by profiling over 300,000 melanoma cells, specifically examining how diverse genetic alterations lead to a shared state of vemurafenib resistance. Their findings highlight a convergent dedifferentiated cell state governed by cooperative transcription factors, such as AP-1 and TEAD, which are activated across various perturbations. Furthermore, the study elucidates how different modules of the Mediator complex uniquely influence cell plasticity and therapeutic response. Ultimately, PerturbFate provides a multimodal framework for uncovering the core molecular nodes that dictate cell-state transitions in cancer.

References:

• Xu Z, Lu Z, Ugurbil A, et al. Mapping convergent regulators of melanoma drug resistance by PerturbFate[J]. Nature, 2026: 1-11.