By spreading an active chromatin state, Pygo2 prompts the proliferation of mammary gland progenitor cells, report Gu et al.
The fly version of Pygo2, Pygopus, is essential for Wg signaling. But the relationship between mammalian Wg (Wnt) and Pygo2 is less clear. Pygo2 is necessary for the development of a number of tissues, but in the two best studied—eye and testis—it has no need for Wnt.
Gu et al. looked at the relationship between Wnt and Pygo2 in mammary gland epithelial cells, where both proteins have been linked with cancer.
Pygo2 was expressed in mammary progenitor cells in the embryo and adult mouse, where it seemed to specifically regulate proliferation. Mammary epithelial cells that lacked Pygo2 still generated mature cell types, despite progenitor cell numbers being reduced.
Is Pygo2's proliferative power driven by Wnt? It seems so. The team found that in mice that lacked Pygo2 in mammary epithelial cells, β-catenin (the cellular effector of Wnt) could no longer induce aberrant proliferation. Wnt target genes were also down-regulated and this correlated with a reduction of histone H3 lysine 4 (H3K4) trimethylation—an epigenetic modification associated with active chromatin. Pygo2 recruited H3K4 methyltransferases, showed the team, and also bound to di- and trimethylated H3K4 suggesting it works in a positive feedback loop to spread the active chromatin mark. This activity was necessary for Pygo2-driven proliferation.
Pygo2's chromatin activity wasn't limited to Wnt targets, however. Pygo2 also associated with histone methyltransferase in bulk chromatin. This suggests Pygo2 is regulated by other pathways, and might explain its Wnt independence in certain tissues.