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Article

Histone Deacetylase 7 and FoxA1 in Estrogen-Mediated Repression of RPRM

, , , , , , , & show all
Pages 399-412 | Received 10 Jul 2009, Accepted 02 Nov 2009, Published online: 20 Mar 2023
 

Abstract

Activation of estrogen receptor α (ERα) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ERα-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ERα, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ERα and represses ERα's transcriptional activity—this repression does not require HDAC7's deacetylase activity. We further show that the chromatin pioneer factor FoxA1, well known for its role in estrogen induction of genes, is recruited to the RPRM promoter, is necessary for repression of RPRM, and interacts with HDAC7. Like other FoxA1 recruitment sites, the RPRM promoter is characterized by H3K4me1/me2. Estrogen treatment causes decreases in H3K4me1/me2 and release of RNA polymerase II (Pol II) from the RPRM proximal promoter. Overall, these data implicate a novel role for HDAC7 and FoxA1 in estrogen repression of RPRM, a mechanism which could potentially be generalized to many more estrogen-repressed genes and hence be important in both normal physiology and pathological processes.

Supplemental material for this article may be found at http://mcb.asm.org/.

This work was supported by a Department of Defense Breast Cancer Research Program grant (BC043880) (S. Malik), NIH grants R01 CA097213 and P01030195 (S. Oesterreich), a SPORE pilot grant (CA58183) (S. Oesterreich), and a Nancy Owen Foundation grant (S. Oesterreich).

We thank Herb Kasler (UCSF) for helpful discussions, Jiemin Wong for the H3K9ac antibody, Chad Creighton for help with the Oncomine Cancer Profiling Database, Steven Johnsen (University of Göttingen) for technical support, and Gary Chamness for critical review of the manuscript.

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