The tumour-suppressive macroH2A histone variants have are thought to function in stem cells, embryonic development and somatic cell reprogramming by stabilizing the differentiated cell state. Although macroH2As have been found to occupy genomic regions with transiently repressive H3K27me3 polycomb marks, the molecular mechanism by which macroH2As uphold differentiation is still unknown. In this issue (p. 1570), Marcus Buschbeck and co-workers find that macroH2As associate with heterochromatin repeats and, in particular, are enriched at binding sites for H3K9me3, a marker for constitutive heterochromatin. Depletion of macroH2As globally reduces heterochromatin density and induces severe defects in nuclear organisation. Without macroH2As, nucleoli are disrupted and domains with DNA repeat sequences are ‘loosened up’ and appear fragmented. Importantly, the authors report that macroH2As interact with the nuclear periphery protein lamin B1, and that this interaction is required for the association of the nuclear lamina with heterochromatic repeats. Taken together, this work describes an important role for macroH2As in the maintenance of heterochromatin organisation and nuclear architecture, providing a framework for the understanding of its roles in cellular reprogramming, development and cancer.
