Acetylation of histone H3K27 signals the transcriptional elongation for estrogen receptor alpha
Open Access
- 7 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Communications Biology
- Vol. 3 (1), 1-10
- https://doi.org/10.1038/s42003-020-0898-0
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R33AI122418)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA211861, P30CA125123)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- American Diabetes Association (1-18-JDF-025)
This publication has 41 references indexed in Scilit:
- Structure of the super-elongation complex subunit AFF4 C-terminal homology domain reveals requirements for AFF homo- and heterodimerizationOnline Journal of Public Health Informatics, 2019
- ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemiaNature, 2017
- ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancerNature Reviews Clinical Oncology, 2015
- Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatinProceedings of the National Academy of Sciences of the United States of America, 2011
- Mechanisms of Endocrine Resistance in Breast CancerAnnual Review of Medicine, 2011
- Histone H3K27ac separates active from poised enhancers and predicts developmental stateProceedings of the National Academy of Sciences of the United States of America, 2010
- Model-based Analysis of ChIP-Seq (MACS)Genome Biology, 2008
- The AP-2 family of transcription factorsGenome Biology, 2005
- AF5q31 , a newly identified AF4 -related gene, is fused to MLL in infant acute lymphoblastic leukemia with ins(5;11)(q31;q13q23)Proceedings of the National Academy of Sciences of the United States of America, 1999
- Characterization of a Dimerization Motif in AP-2 and Its Function in Heterologous DNA-Binding ProteinsScience, 1991