Fat cadherin cleavage releases a transcriptionally active nuclear fragment to regulate target gene expression

The atypical cadherin fat (ft) controls growth, planar cell polarity (PCP) tissue organization, and mitochondrial function, in organisms ranging from fruit flies to mammals. Working at the apical-junctional plasma membrane, the intracellular domain of the Ft protein, FtICD binds to and regulates components of the Hippo and PCP pathways. Unexpectedly, we find that a fragment of the FtICD is present in the nucleus in cultured cells as well as in embryonic and larval tissues and identify nuclear localization and nuclear export signals in FtICD required for this localization. We show membrane-bound FtICD is cleaved and enters nuclei in vivo. Using endogenously tagged Ft as well as overexpressed FtICD we conducted ChIP-seq experiments and identified putative Ft targets including genes involved in signaling pathways, chromatin organization, pattern formation, and neural development. RNAseq demonstrates that some of these genes are dysregulated in ft mutants. We observe strong co-localization of Ft binding regions with peaks for other factors such as DREF and BEAF-32, as well as the Hippo pathway components Yorkie (Yki) and Scalloped (Sd), suggesting that Ft may act in conjunction with these factors to regulate gene expression. Supporting this hypothesis, we found that Ft physically interacts with both Yki and Sd in co-immunoprecipitation experiments in S2 cells. We propose that the modulation of Hippo pathway activity constitutes one of the nuclear functions of Ft, complementing its established function as an upstream regulator of Hippo signaling. Overall design: RNA-seq profiling of Drosophila 16-20 h embryo. This dataset is used to compare w^1118 (wild-type) and ft^fd5-5/ft^X13 (Ft null mutants).