Complex-specific inhibitors for interrogating ATAC histone acetyltransferase complex

Histone acetyltransferases (HATs) modify chromatin to regulate gene expression. Instead of acting alone, HATs function in complexes with other proteins, leading to variations in substrate specificity, genomic localization and cellular function. To understand the complex-dependent roles of HATs, we present a chemical approach to specifically dissociate ATAC (Ada-two-A-containing) HAT complex from chromatin without perturbing other complexes. Rather than targeting the shared HAT enzyme, we developed chemical inhibitors for an ATAC-specific subunit, YEATS2. The most effective inhibitor, LS-170, specifically reduced the chromatin occupancy of the ATAC complex, decreased the ATAC-dependent histone acetylation level and downregulated the expression of ATAC-governed genes, leading to significantly suppressed tumor growth in a lung cancer mouse model. This study not only sheds light on the regulatory roles of the ATAC HAT complex in gene transcription but also provides evidence that the chemical inhibition of the ATAC complex can be a promising therapeutic strategy.