Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification

In mammalian cells, gene copy number is controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, increasing the copy number and expression of tumor-promoting genes and thus promoting cancer progression. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification is frequent. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the underlying mechanisms are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identify a global chromatin-priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading and inter-TAD interactions, which occur before the onset of oncogene amplification. Furthermore, we show that METTL7A, reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. METTL7A appears to remodel the chromatin landscape prior to large-scale copy number gains. Although METTL7A depletion exerts little phenotypical effects on drug-naive cells, its depletion prevents the formation and maintenance of TKI resistant-clones, showcasing its role as cells become resistant. In summary, we unveil a mechanism required for the acquisition of TKI resistance regulated by an unexpected chromatin function of METTL7A.