Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha

As approximately 70% of human breast tumors are estrogen receptor a (ERa)-positive, estrogen and ERa play essential roles in breast cancer development. By interrupting the ERa signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In the present study, we identified a novel mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ERa gene. The SEC interacts with H3K27ac on ERa TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ERa and its target genes, consequently inhibiting breast cancer cell growth. More importantly, AFF4 mutant which lacks H3K27ac interaction failed to rescue ERa gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERa signaling pathway at the level of chromatin. Overall design: Examination of chromatin association of AFF4 and histone H3K27 acetylation in MCF7 breast cancer cell line