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

Abstract

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 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 ERα signaling pathway at chromatin level.

Estrogen Induces Selective Transcription of Caveolin1 Variants in Human Breast Cancer through Estrogen Responsive Element-Dependent Mechanisms

“…Our data highlighted that all ERE regions show discrete oscillations of H3K4 methylation and H3K9 de-methylation, ensuing proper transcription. Active enhancer-like regions are also marked by H3K27Ac signature [ 44 ] and we also found enrichment of histone H3K27 acetylation (H3K27ac) on the three EREs, with oscillatory kinetics.…”

“…To extend our analysis on the identified regions with possible enhancer function, we examined the profile of acetylation on Lys27 in H3 (H3K27Ac), as active chromatin epigenetic signature [ 44 ]. The kinetics of H3K27Ac shows that, following E2 exposure it accumulates at ERE1 and ERE3 sites, with two sharp peaks at 15 and 45 min ( Figure 4 g).…”

Respiratory Syncytial Virus Infection Induces Chromatin Remodeling to Activate Growth Factor and Extracellular Matrix Secretion Pathways

“…Substantial Tn5 transposase cleavage is seen on the IL6, TSLP, CCL20, and MIP1α promoters, and these promoters overlap experimentally determined H3K27Ac and RNA Pol II peaks. H3K27 marks are characteristic of inducible promoters bound by the positive transcriptional elongation factor [37]. With promoters in an open chromatin environment engaged with RNA Pol II, activated NFκB, STAT, and IRF are able to induce high level of expression in response to RSV infection.…”

Promoter-specific changes in initiation, elongation and homeostasis of histone H3 acetylation during CBP/p300 Inhibition

“…SEC recruitment at E4 by H3K18/27ac may be due to interactions with acetyl-lysine-binding YEATS domains present in the AF9 and ENL SEC subunits (14,15), but other SEC components may also contribute. For example, the SEC was reported to be recruited to chromatin with H3K27ac through an interaction with the Cterminus of the central scaffold protein AFF4 at the TSS of the estrogen receptor 1 gene (ESR1) in cultured breast cancer cells (33).…”