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Abstract

Canonical Wnt signaling is repeatedly used during development to control cell fate, and it is often implicated in human cancer. β-catenin, the effector of Wnt signaling, has a dual function in the cell and is involved in both cell adhesion and transcription. Nuclear β-catenin controls transcription through association with transcription factors of the TCF family and the recruitment of epigenetic modifiers. In this study, we used a strategy combining the genetic manipulation of mouse embryonic stem cells with affinity purification and quantitative mass spectroscopy utilizing stable isotope labeling with amino acids in cell culture to study the interactome of chromatin-bound β-catenin with and without Wnt3a stimulation. We uncovered previously unknown interactions of β-catenin with transcription factors and chromatin-modifying complexes. Our proof-of-principle experiments show that β-catenin can recruit the H3K4me2/1 demethylase LSD1 to regulate the expression of the tumor suppressor Lefty1 in mouse embryonic stem cells. The mRNA levels of LSD1 and β-catenin are inversely correlated with the levels of Lefty1 in pancreas and breast tumors, implying that this mechanism is common to mouse embryonic stem cells and cancer cells.