A complex epigenome-splicing crosstalk governs epithelial to mesenchymal transition in metastasis and brain development

Epithelial to Mesenchymal Transition (EMT) renders epithelial cells migratory properties. While epigenetic and splicing changes have been implicated in EMT, the mechanisms governing their crosstalk remain poorly understood. Here, we discovered a C2H2 zinc finger protein, ZNF827, is strongly induced during various contexts of EMT including in brain development and breast cancer metastasis and is required for the molecular and phenotypic changes underlying EMT in these processes. Mechanistically, ZNF827 mediated these responses by orchestrating a large-scale remodeling of the splicing landscape by recruiting HDAC1 for epigenetic modulation of distinct genomic loci, thereby slowing RNA Pol II progression and altering the splicing of genes encoding key EMT regulators in cis. Our findings reveal an unprecedented complexity of crosstalk between epigenetic landscape and splicing programme in governing EMT and identify ZNF827 as a master regulator coupling these processes during EMT in brain development and breast cancer metastasis. Overall design: RNA-seq ChIP-seq, CUT&TAG and fastGRO analysis of HMLE cells following ZNF827 depletion during TGFbeta-induced EMT