Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM.
Activation of estrogen receptor alpha (ERalpha) 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 ERalpha-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 ERalpha, histone deacetylase 7 (HDAC7), and FoxA1. HDAC7 is the critical HDAC needed for repression of RPRM; it can bind to ERalpha and represses ERalpha'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.
Malik
Simeen
S
Department of Molecular and Cellular Biology, 3 Baylor College of Medicine, Houston, Texas 77030, USA.
Jiang
Shiming
S
Garee
Jason P
JP
Verdin
Eric
E
Lee
Adrian V
AV
O'Malley
Bert W
BW
Zhang
Mao
M
Belaguli
Narasimhaswamy S
NS
Oesterreich
Steffi
S
D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D000077267:Fulvestrant; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000187:drug effects / Q000378:metabolism*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012319:RNA Polymerase II / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D018797:Cell Cycle Proteins; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D004967:Estrogens; C496499:FOXA1 protein, human; D006023:Glycoproteins; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; C412566:RPRM protein, human; D000077267:Fulvestrant; D004958:Estradiol; D012319:RNA Polymerase II; C543273:HDAC7 protein, human; D006655:Histone Deacetylases