Project description:Genome-wide chromatin analyses to validate the CRISPR interference screen for modulators of mesenchymal signaling reporter in A549 and H1944 cells. ATAC-seq in naive, GSK126- and TGFB-treated A549 cells. ChIP-seq in naive A549 cells for chromatin modulators, ChIP-seq in naive and GSk126-treated cells from RNAPII in A549 cells.
Project description:Genome-wide chromatin analyses to validate the CRISPR interference screen for modulators of mesenchymal signaling reporter in A549 and H1944 cells. ATAC-seq in naive, GSK126- and TGFB-treated A549 cells. ChIP-seq in naive A549 cells for chromatin modulators, ChIP-seq in naive and GSk126-treated cells from RNAPII in A549 cells.
Project description:Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state-specific therapy.
