Gene-Specific Patterns of Coregulator Requirements by Estrogen Receptor-α in Breast Cancer Cells

Abstract

Progesterone receptor (PgR) controls the menstrual cycle, pregnancy, embryonic development, and homeostasis, and it plays important roles in breast cancer development and progression. However, the requirement of coregulators for estrogen-induced expression of the PgR gene has not been fully explored. Here we used RNA interference to demonstrate dramatic differences in requirements of 10 different coregulators for estrogen-regulated expression of six different genes, including PgR and the well-studied TFF1 (or pS2) gene in MCF-7 breast cancer cells. Full estrogen-induced expression of TFF1 required all ten coregulators, but PgR induction required only four of the 10 coregulators. Chromatin immunoprecipitation studies demonstrated several mechanisms responsible for the differential coregulator requirements. Actin-binding coregulator Flightless-I, required for TFF1 expression and recruited to that gene by estrogen receptor-α (ERα), is not required for PgR expression and not recruited to that gene. Protein acetyltransferase tat-interactive protein 60 and ATP-dependent chromatin remodeler Brahma Related Gene 1 are recruited to both genes but are required only for TFF1 expression. Histone methyltransferase G9a is recruited to both genes and required for estrogen-induced expression of TFF1 but negatively regulates estrogen-induced expression of PgR. In contrast, histone methyltransferase myeloid/lymphoid or mixed-lineage leukemia 1 (MLL1), pioneer factor Forkhead box A1, and p160 coregulator steroid receptor coactivator-3 are required for expression of and are recruited to both genes. Depletion of MLL1 decreased ERα binding to the PgR and TFF1 genes. In contrast, depletion of G9a enhanced ERα binding to the PgR gene but had no effect on ERα binding to the TFF1 gene. These studies suggest that differential promoter architecture is responsible for promoter-specific mechanisms of gene regulation.

Expressomal approach for comprehensive analysis and visualization of ligand sensitivities of xenoestrogen responsive genes

“…S6. Transcriptional activation or suppression by estrogen receptors (ERs) involves differential recruitments of specific coregulators on different target genes (26). Specific DNA base sequences at and around the ER binding sites serve as allosteric modulators of ER conformation and thereby affect selection of coregulator recruitment and transcriptional activities (27).…”

Hic-5 is a transcription coregulator that acts before and/or after glucocorticoid receptor genome occupancy in a gene-selective manner

“…ChIP was performed as described (6). Primers for GBRs were designed using the data deposited in the National Center for Biotechnology Information's Sequence Read Archive via accession number SRP020242.…”

“…Current evidence suggests that scores of coregulators cooperate in the transcriptional regulation of each gene, with each coregulator contributing a specific molecular function, e.g., remodeling of chromatin or transcription complex assembly/disassembly (1). Moreover, coregulators act gene specifically, using different activation and repression domains to perform different actions on different genes, as specified by the bound GR (2)(3)(4)(5)(6). Protein allostery and the combinatorial nature of transcriptional regulation are responsible for the gene specificity of receptor and coregulator function (7,8), but the specific steps facilitated by a coregulator in a given context are mostly unknown.…”

Estrogen Receptor β (ERβ1) Transactivation Is Differentially Modulated by the Transcriptional Coregulator Tip60 in a cis-Acting Element-dependent Manner

“…Moreover, Tip60 functions as either a coactivator (22)(23)(24)(25)(26) or a corepressor (27,28), depending on its interacting transcription factors. Tip60 enhances ER␣ transactivation at ERE sites in a ligand-dependent manner (29,30) and thus increases the expression of certain ER␣ target genes (29,31). A study also shows that Tip60 interacts with ER␤1 in the presence of estrogen (32).…”