Brown Myles, Akhshi Tara, Hu Shengen Shawn, Wheeler Esme, Hellriegel Christian, Richardson Douglas S, Cayting Nicole, Mvula Wangu, Ahmed Buraq, Jeselsohn Rinath, Zang Chongzhi
Dana-Farber Cancer Institute.
University of Virginia.
Res Sq. 2025 Jun 17:rs.3.rs-6804567. doi: 10.21203/rs.3.rs-6804567/v1.
Changes in gene expression regulated by ligand-dependent transcription factors such as estrogen receptor-α (ERα) involves the recruitment of coactivators including p300 that acetylates histone H3 at lysine 27 (H3K27ac). While H3K27ac marks active enhancers, the detailed chromatin architecture of enhancers remains unclear. Using super-resolution microscopy, we reveal distinct structural states of H3K27ac modified chromatin in response to ERα activation. In estradiol (E2)-treated cells, H3K27ac modified chromatin adopts open, elongated structures associated with active enhancers, while ERα inhibition induces compact, spherical H3K27ac modified chromatin conformations linked to repression. A constitutively active ERα mutation linked to endocrine therapy resistance in breast cancer maintains open chromatin states independent of ligand, suggesting sustained transcriptional activity. Our findings provide the first direct visualization of H3K27ac associated chromatin structural dynamics, challenging the assumption that H3K27ac modification alone is sufficient to lead to enhancer activation. By demonstrating that H3K27ac architecture is dynamically regulated by ERα, we establish a new paradigm for understanding epigenetic regulation and highlight potential therapeutic targets for endocrine therapy resistant cancers.
由雌激素受体-α（ERα）等配体依赖性转录因子调控的基因表达变化涉及共激活因子的募集，包括使组蛋白H3赖氨酸27位点（H3K27ac）乙酰化的p300。虽然H3K27ac标记活跃的增强子，但增强子的详细染色质结构仍不清楚。利用超分辨率显微镜，我们揭示了响应ERα激活的H3K27ac修饰染色质的不同结构状态。在经雌二醇（E2）处理的细胞中，H3K27ac修饰的染色质呈现与活跃增强子相关的开放、细长结构，而ERα抑制则诱导与抑制相关的紧凑、球形H3K27ac修饰染色质构象。与乳腺癌内分泌治疗耐药相关的组成型活性ERα突变维持独立于配体的开放染色质状态，表明存在持续的转录活性。我们的研究结果首次直接观察到H3K27ac相关的染色质结构动态变化，挑战了仅H3K27ac修饰就足以导致增强子激活的假设。通过证明H3K27ac结构受ERα动态调控，我们建立了一种理解表观遗传调控的新范式，并突出了内分泌治疗耐药癌症的潜在治疗靶点。
