Abstract
Chromatin constitutes a repressive barrier to the process of ligand-dependent transcriptional activity of nuclear receptors. Nucleosomes prevent the binding of estrogen receptor α (ERα) in absence of ligand and thus represent an important level of transcriptional regulation. Here, we show that in breast cancer MCF-7 cells, TLE3, a co-repressor of the Groucho/Grg/TLE family, interacts with FoxA1 and is detected at regulatory elements of ERα target genes in absence of estrogen. As a result, the chromatin is maintained in a basal state of acetylation, thus preventing ligand-independent activation of transcription. In absence of TLE3, the basal expression of ERα target genes induced by E2 is increased. At the TFF1 gene, the recruitment of TLE3 to the chromatin is FoxA1-dependent and prevents ERα and RNA polymerase II recruitment to TFF1 gene regulatory elements. Moreover, the interaction of TLE3 with HDAC2 results in the maintenance of acetylation at a basal level. We also provide evidence that TLE3 is recruited at several other regulatory elements of ERα target genes and is probably an important co-regulator of the E2 signaling pathway. In sum, our results describe a mechanism by which TLE3 affects ligand dependency in ERα-regulated gene expression via its binding restricting function and its role in gene regulation by histone acetylation.
Highlights
Estrogen is the ligand for the nuclear receptor estrogen receptor alpha (ER␣) and is implicated in various pathologies such as osteoporosis and breast, ovarian and endometrial cancers [1]
The authors showed that an H3K9me3 and H3K4me1/2 demethylase named LSD1 was present in the vicinity of most ER␣activated genes to counteract the effects of several histone methyl transferases (HMTs) whose function is to establish a chromatin state unfavorable for transcription activation
This co-expression was observed in breast cancer primary tumors (Supplementary Figure S1C). These observations suggest that TLE3 and ER␣ expression are associated despite the fact that the TLE3 gene is not regulated by estrogen (E2) (Supplementary Figure S2A and S2B)
Summary
Estrogen is the ligand for the nuclear receptor estrogen receptor alpha (ER␣) and is implicated in various pathologies such as osteoporosis and breast, ovarian and endometrial cancers [1]. Upon its induction by estrogen, ER␣ binds to DNA regulatory elements and activates or represses its target genes expression [2]. To prevent inappropriate transcription events, ER␣ activity is tightly regulated by several mechanisms among which chromatin and co-factors binding play crucial roles. In 2007, a study of the epigenetic landmarks found around ER␣ target genes in MCF-7 cells highlighted the importance of histones post-translational modifications in ligand-dependent gene activation, histone methylation. HMTs were maintained around regulatory elements to methylate histone tails and prevent constitutive gene activation. LSD1 was recruited to remove the inhibitory marks and allow liganded ER␣ to stimulate the transcription of its target genes, demonstrating the importance of posttranslational modifications of histones, methylation, in ligand-dependent gene activation [6]
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