Department of Chemistry, Princeton University, Princeton, NJ, USA.
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY, USA.
Nat Chem Biol. 2021 Apr;17(4):403-411. doi: 10.1038/s41589-021-00738-1. Epub 2021 Mar 1.
Whole-genome sequencing data mining efforts have revealed numerous histone mutations in a wide range of cancer types. These occur in all four core histones in both the tail and globular domains and remain largely uncharacterized. Here we used two high-throughput approaches, a DNA-barcoded mononucleosome library and a humanized yeast library, to profile the biochemical and cellular effects of these mutations. We identified cancer-associated mutations in the histone globular domains that enhance fundamental chromatin remodeling processes, histone exchange and nucleosome sliding, and are lethal in yeast. In mammalian cells, these mutations upregulate cancer-associated gene pathways and inhibit cellular differentiation by altering expression of lineage-specific transcription factors. This work represents a comprehensive functional analysis of the histone mutational landscape in human cancers and leads to a model in which histone mutations that perturb nucleosome remodeling may contribute to disease development and/or progression.
全基因组测序数据挖掘工作揭示了多种癌症类型中大量的组蛋白突变。这些突变发生在核心组蛋白的尾部和球状结构域的所有四个亚基中，且大部分特征尚未明确。在这里，我们使用了两种高通量方法，即 DNA 编码单核小体文库和人源化酵母文库，来研究这些突变的生化和细胞效应。我们鉴定了在组蛋白球状结构域中与癌症相关的突变，这些突变增强了基本的染色质重塑过程、组蛋白交换和核小体滑动，并且在酵母中是致死的。在哺乳动物细胞中，这些突变通过改变谱系特异性转录因子的表达而上调与癌症相关的基因通路，并抑制细胞分化。这项工作代表了对人类癌症中组蛋白突变景观的全面功能分析，并提出了一个模型，即扰乱核小体重塑的组蛋白突变可能导致疾病的发生和/或进展。
