SRC-3 Coactivator Governs Dynamic Estrogen-Induced Chromatin Looping Interactions during Transcription

Molecular Cell
Anil K PanigrahiBert W O'Malley

Abstract

Enhancers are thought to activate transcription by physically contacting promoters via looping. However, direct assays demonstrating these contacts are required to mechanistically verify such cellular determinants of enhancer function. Here, we present versatile cell-free assays to further determine the role of enhancer-promoter contacts (EPCs). We demonstrate that EPC is linked to mutually stimulatory transcription at the enhancer and promoter in vitro. SRC-3 was identified as a critical looping determinant for the estradiol-(E2)-regulated GREB1 locus. Surprisingly, the GREB1 enhancer and promoter contact two internal gene body SRC-3 binding sites, GBS1 and GBS2, which stimulate their transcription. Utilizing time-course 3C assays, we uncovered SRC-3-dependent dynamic chromatin interactions involving the enhancer, promoter, GBS1, and GBS2. Collectively, these data suggest that the enhancer and promoter remain "poised" for transcription via their contacts with GBS1 and GBS2. Upon E2 induction, GBS1 and GBS2 disengage from the enhancer, allowing direct EPC for active transcription.

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Citations

Aug 14, 2019·PloS One·Murugesan PalaniappanCristian Coarfa
Sep 4, 2019·Nature Genetics·Shigeki HirabayashiYasuhiro Murakawa
May 2, 2020·The Journal of Biological Chemistry·Sylvia C HewittKenneth S Korach
Aug 30, 2018·International Journal of Molecular Sciences·Meng ChengRamakrishna Kommagani
Sep 6, 2020·Trends in Biochemical Sciences·Tim Y Hou, W Lee Kraus
Apr 17, 2021·Genome Biology·Anil Panigrahi, Bert W O'Malley
May 6, 2021·International Journal of Molecular Sciences·Licen LiQiang Chen
Jan 2, 2021·Current Opinion in Cell Biology·Leonid Serebreni, Alexander Stark
Aug 28, 2021·Genes·Amarni L ThomasJulia A Horsfield

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