Pygopus2-Histone interaction is important for de-differentiation and breast cancer progression [ATAC-Seq]

Pygopus2 (Pygo2), a co-activator of Wnt/ β-catenin signaling can also bind H3K4me2/3 and participate in chromatin reading and writing. To investigate the functional relevance of histone binding activity of Pygo2 in malignant progression of breast cancer, we generated a knockin mouse model wherein binding of Pygo2 to H3K4me2/3 was rendered ineffective. Loss of Pygo2-histone binding resulted in smaller, differentiated and less metastatic tumors, at least in part due to a decrease in Wnt/ b-catenin signaling. RNA and ATAC-Seq analyses of tumor-derived cell lines revealed a downregulation of TGFb signaling and an upregulation of differentiation pathways like PDGFR. This also correlated with an increase in luminal cell fate which could be rescued by inhibition of the PDGFR pathway. Mechanistically, we find that Pygo2-histone interaction is important for expression of mir-29 family members to potentiate Wnt/ b-catenin signaling by suppressing Wnt signaling antagonists expression in addition to suppression of PDGFR expression. Collectively, our results demonstrate that histone binding function of Pygo2 is important for driving de-differentiation and malignancy of breast tumors and loss of this binding activates differentiation pathways that lead to decreased tumor growth and metastases. Ablating the Pygo2-H3K4me3 interaction hence might serve as an attractive therapeutic target for breast cancer. ATAC-Seq of Pygo2+/+ (WT) and Pygo2 AE/AE mutant cell lines on treatment with TGFb or Wnt3a was performed in biological duplicates