近日，美国洛克菲勒大学曹俊越团队研究出通过摄动绘制黑色素瘤耐药的收敛调节因子。相关论文于2026年4月15日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组人员提出了一个高通量、高成本效益、组合索引的单细胞平台，它可以系统地询问从染色质重塑和新生转录到稳态转录组表型的基因调控全谱中的大规模平行CRISPR干扰。使用摄动命运，小组分析了超过30万个培养的黑色素瘤细胞，以表征140多个vemurafenib耐药相关基因对扰动的多模态表型和基因调控反应。

该课题组发现了一种共同的去分化细胞状态，其特征是不同遗传扰动下的趋同合作转录因子活性。研究小组进一步剖析了对中介复合物组分扰动的表型反应，将模块特异性生化特性与趋同转录激活联系起来。研究人员确定了在不同的遗传扰动中驱动相似表型结果的共同调控节点。小组还描述了功能无关基因的扰动如何重塑细胞状态。他们，微扰建立了一个通用平台，通过锚定多模态调控动力学到疾病相关表型来识别关键的分子调控。

据了解，高通量基因组研究揭示了多种遗传改变与疾病表型之间的关联。然而，阐明功能不同基因的扰动如何引起细胞状态趋同仍然具有挑战性。

附：英文原文

Title: Mapping convergent regulators of melanoma drug resistance by PerturbFate

Author: Xu, Zihan, Lu, Ziyu, Ugurbil, Aileen, Abdulraouf, Abdulraouf, Liao, Andrew, Zhang, Jianxiang, Zhou, Wei, Cao, Junyue

Issue&Volume: 2026-04-15

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

Source: https://www.nature.com/articles/s41586-026-10367-0