EZH2 mutations increase the heterogeneity of chromatin states in lymphoma

Abstract

A recent study in PLoS Biology used simultaneous measurements of histone modifications in single cells to reveal that EZH2 gain-of-function mutations profoundly reprogram chromatin states in B-cell lymphoma, while also increasing their cell-cell heterogeneity.

Fig 1. Cytometry by Time of Flight reveals epistasis and heterogeneity.

(A) In Cytometry by Time of Flight (CyTOF), cells are stained with metal-conjugated antibodies, here mainly targeting modified histones, and epitope abundance is then quantified in multiplex in large numbers of individual cells. The data can be analyzed mark by mark, as well as across all the marks using dimensionality reduction approaches, to reveal subpopulations and assess heterogeneity. (B) Griess and colleagues explore the consequences of KMT2D null and EZH2 gain-of-function mutations on histone modification profiles in lymphoma cells using CyTOF. They discover that EZH2 alterations are epistatic to KMT2D loss of function (see text) and increase both the epigenomic and transcriptomic heterogeneity of the cells. They identify “extreme” and “WT-like” subpopulations of EZH2-mutant cells that form dynamically and show distinct responses to small-molecule inhibitors.