Michael Mancini, Ph.D.
Baylor College of Medicine
NIEHS grantees found that individual cells in a population respond differently to estrogen stimulation at both the level of single cells and alleles, which are other possible forms of a gene. These differences were not explained by estrogen receptor levels in the cells or its activation status.
The researchers treated human breast cancer cells with estrogen in the lab and looked at expression of two well-characterized genes, GREB1 and MYC, whose activities are regulated by estrogen. As expected, they found that estrogen activated GREB1 and MYC genes within 15 minutes. Unexpectedly, individual cells exhibited large differences in the level of gene activation. These differences occurred even between alleles within the same cell.
To determine whether estrogen receptor regulators were involved in modifying the response to estrogen, the scientists used automated high-throughput technologies to test a collection of small molecule inhibitors of the estrogen receptor regulators. One inhibitor, called MS049, markedly increased the response of individual alleles to estrogen.
The researchers altered estrogenic response by inhibiting estrogen receptor regulators, establishing a previously unrecognized regulation path for estrogen to activate genes at the single cell level. According to the authors, the findings provide novel insights into the complex ways that cells maintain variability in response to stimuli, an important adaptation strategy for cell populations.
Citation: Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. 2020. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Nucleic Acids Res 48(4):1800–1810.