美国威斯康星大学Srivatsan Raman和Zachary Morris研究组近日取得一项新成果。他们发现由癌融合蛋白和其它编码蛋白质的变异引起的染色质失调。相关论文于2024年7月24日发表在《自然—生物技术》杂志上。

该团队提出了PROD-ATAC，一种用于发现蛋白质编码变体对染色质调控影响的高通量方法。汇集的变体库在疾病不可知的细胞系中表达，转座酶可及染色质的单细胞测定解决了每个变体对染色质图谱的影响。使用PROD-ATAC，研究组表征了100多种癌融合蛋白（致癌嵌合蛋白）和对照组的影响，发现染色质重塑在涉及广泛融合频率的融合中是常见的。

此外，融合诱导的失调可能与环境无关，因为观察到的机制经常与癌症和细胞类型特异性的先前知识重叠。课题组研究人员还发现，功能获得活性在肿瘤细胞中很常见。这项工作开始勾勒出融合诱导的染色质改变的整体图谱。研究小组认为在不同的肿瘤细胞之间可能存在趋同机制，在不同频率的肿瘤细胞中可能存在共同的失调模式。PROD-ATAC可推广到任何一组蛋白质编码变体。

研究人员表示，人口规模的数据库已经扩展到数以百万计的蛋白质编码变体，但对其机制结果的了解却滞后。

附：英文原文

Title: Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants

Author: Frenkel, Max, Corban, James E., Hujoel, Margaux L. A., Morris, Zachary, Raman, Srivatsan

Issue&Volume: 2024-07-24

Abstract: Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant’s effect on the chromatin landscape. Using PROD-ATAC, we characterized the effects of more than 100 oncofusions (cancer-causing chimeric proteins) and controls and revealed that chromatin remodeling is common to fusions spanning an enormous range of fusion frequencies. Furthermore, fusion-induced dysregulation can be context agnostic, as observed mechanisms often overlapped with cancer and cell-type-specific prior knowledge. We also showed that gain-of-function activity is common among oncofusions. This work begins to outline a global map of fusion-induced chromatin alterations. We suggest that there might be convergent mechanisms among disparate oncofusions and shared modes of dysregulation among fusions present in tumors at different frequencies. PROD-ATAC is generalizable to any set of protein-coding variants.

DOI: 10.1038/s41587-024-02347-4

Source: https://www.nature.com/articles/s41587-024-02347-4