The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled
histones with
histone variants is the least understood. Due to differences in
protein sequence and genomic distribution,
histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of
macroH2A histone variants that are particular in having a tripartite structure consisting of a
histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to
chromatin architecture, transcription and DNA repair. Dysregulated expression of
macroH2A histone variants has been observed in different subtypes of
cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and
isoform-dependent contributions of
macroH2A histone variants to
cancer development and progression.