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

ABSTRACT: As approximately 70% of human breast tumors are estrogen receptor ? (ER?)-positive, estrogen and ER? play essential roles in breast cancer development. By interrupting the ER? 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 (ER?) 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 ER? signaling pathway at chromatin level.

SUBMITTER: Gao Y

PROVIDER: S-EPMC7138820 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Gao Yujing Y Chen Lijia L Han Yali Y Wu Fangrui F Yang Wen-Si WS Zhang Zheng Z Huo Tong T Zhu Yingmin Y Yu Chengtai C Kim Hong H Lee Mark M Tang Zhen Z Phillips Kevin K He Bin B Jung Sung Yun SY Song Yongcheng Y Zhu Bokai B Xu Rui-Ming RM Feng Qin Q

Communications biology 20200407 1

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 in ...[more]

PMID: 32265480

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Project description:Despite clinical advances, ischemia-induced cardiac diseases remain an underlying cause of death worldwide. Epigenetic modifications, especially alterations in the acetylation of histone proteins play a pivotal role in counteracting stressful conditions, including ischemia. In our study, we found that histone active mark H3K27ac was significantly reduced and histone repressive mark H3K27me3 was significantly upregulated in the cardiomyocytes exposed to the ischemic condition. Then, we performed a high throughput drug screening assay using rat ventricular cardiomyocytes during the ischemic condition and screened an antioxidant compound library comprising of 84 drugs for H3K27ac by fluorescence microscopy. Our data revealed that most of the phenolic compounds like eugenol, apigenin, resveratrol, bis-demethoxy curcumin, D-gamma-tocopherol, ambroxol, and non-phenolic compounds like l-Ergothioneine, ciclopirox ethanolamine, and Tanshinone IIA have a crucial role in maintaining the cellular H3K27ac histone marks during the ischemic condition. Further, we tested the role of eugenol on cellular protection during ischemia. Our study shows that ischemia significantly reduces cellular viability and increases total reactive oxygen species (ROS), and mitochondrial ROS in the cells. Interestingly, eugenol treatment significantly restores the cellular acetylation at H3K27, decreases cellular ROS, and improves cellular viability. To explore the mechanism of eugenol-medicated inhibition of deacetylation, we performed a RNAseq experiment. Analysis of transcriptome data using IPA indicated that eugenol regulates several cellular functions associated with cardiovascular diseases, and metabolic processes. Further, we found that eugenol regulates the expression of HMGN1, CD151 and Ppp2ca genes during ischemia. Furthermore, we found that eugenol might protect the cells from ischemia through modulation of HMGN1 protein expression, which plays an active role in regulation of histone acetylation and cellular protection during stress. Thus, our study indicated that eugenol can be exploited as an agent to protect the ischemic cells and also could be used to develop a novel drug for treating cardiac disease.

Dataset Information

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

Publications

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

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