Alternatively Constructed Estrogen Receptor Alpha-Driven Super-Enhancers Result in Similar Gene Expression in Breast and Endometrial Cell Lines.

Dóra Bojcsuk,Gergely Nagy,Bálint László Bálint

doi:10.3390/ijms21051630

Dóra Bojcsuk, Gergely Nagy + Show 1 more

Open Access

https://doi.org/10.3390/ijms21051630

Copy DOI

Abstract

Super-enhancers (SEs) are clusters of highly active enhancers, regulating cell type-specific and disease-related genes, including oncogenes. The individual regulatory regions within SEs might be simultaneously bound by different transcription factors (TFs) and co-regulators, which together establish a chromatin environment conducting to effective transcription. While cells with distinct TF profiles can have different functions, how different cells control overlapping genetic programs remains a question. In this paper, we show that the construction of estrogen receptor alpha-driven SEs is tissue-specific, both collaborating TFs and the active SE components greatly differ between human breast cancer-derived MCF-7 and endometrial cancer-derived Ishikawa cells; nonetheless, SEs common to both cell lines have similar transcriptional outputs. These results delineate that despite the existence of a combinatorial code allowing alternative SE construction, a single master regulator might be able to determine the overall activity of SEs.

Highlights

Estrogen receptor alpha (ERα) is a well-studied member of the nuclear receptor (NR) superfamily and functions as a master regulator in several cell types, including breast, ovarian, and endometrial cancer cells [1,2,3]
By testing the similarities between MCF-7 and Ishikawa cells at the level of ERα cistromes upon E2 treatment, we found that both cell lines had tens of thousands of ERα transcription factor binding sites (TFBSs), but most of these sites were characteristic of only one of the investigated cell lines (Figure 1A)
As SEs are responsible for cell identity, understanding their mechanism of action is indispensable for improving our knowledge of the regulation of gene expression in general and cellular identity in particular [24]

Summary

Introduction

Estrogen receptor alpha (ERα) is a well-studied member of the nuclear receptor (NR) superfamily and functions as a master regulator in several cell types, including breast, ovarian, and endometrial cancer cells [1,2,3]. The continuously changing level of its natural ligand, 17β-estradiol (E2), is indispensable for maintaining the ovarian cycle, and normal hormone levels are responsible for female characteristics and contribute to healthy bone density among others, a higher estrogen/progesterone ratio in breast and endometrial tissues is linked to an increased risk of breast and endometrial cancer in postmenopausal women [4,5,6]. DNA binding by the receptor/ligand complex can occur directly through the estrogen response element (ERE) or via indirect protein-protein interactions [7,8,9,10,11]. High-affinity elements or canonical elements can immobilize the transcription factor (TF), exerting a much greater influence on gene expression than the weaker elements that most likely need other stabilizing TFs to generate the activator complex or indirect DNA-protein interactions where an association with other TFs is required [15,16]

Methods

Results

Conclusion