FoxA1 binding to the MMTV LTR modulates chromatin structure and transcription

Holmqvist, Per-Henrik; Беликов, С.; Zaret, Kenneth S.; Wrange, Oerjan

doi:10.1016/j.yexcr.2004.12.002

Cited by 35 publications

(32 citation statements)

References 34 publications

(61 reference statements)

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“…FoxA1 binding in the presence of GR resulted in the formation of a hormone-dependent enlarged enhanceosome complex. We also showed that FoxA1 partially inhibited the transcription of hormone-activated MMTV LTR (23). However, recent FoxA1 and GR titration experiments showed that FoxA1 stimulates hormone-induced MMTV transcription at low GR concentrations (see Fig.…”

mentioning

confidence: 51%

“…The C-terminal domain of the protein was reported to interact with core histones H3 and H4 and to contribute to its ability to mediate an open chromatin in a non-ATP-dependent manner in vitro (12). Recently, we reported on two FoxA1 sites in two separate locations within the MMTV LTR, i.e., in the Ϫ225 position and the location comprising positions Ϫ51 to Ϫ39 (Ϫ51/Ϫ39) relative to the transcription start site (23). When expressed in oocytes from Xenopus laevis, the FoxA1 was able to bind both to the inactive and to the hormone-activated MMTV LTR.…”

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confidence: 99%

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FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter

Беликов

Åstrand

Wränge

2009

Molecular and Cellular Biology

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Reconstitution of the glucocorticoid receptor (GR)-regulated mouse mammary tumor virus (MMTV) promoter in Xenopus oocytes was used to monitor the effects of different transcription factor contexts. Three constitutively binding factors, nuclear factor 1 (NF1), octamer transcription factor 1 (Oct1), and the Forkhead box A1 (FoxA1), were shown to act in concert, to direct the chromatin structure, and to enhance the GR response. FoxA1 has a dominant effect in the absence of hormone and induces a cluster of DNase I-hypersensitive sites in the segment comprising bp ؊400 to ؉25. This FoxA1-mediated chromatin remodeling does not induce MMTV transcription, as opposed to that of the GR. However, the robust FoxA1-dependent chromatin opening has the following drastic functional consequences on the hormone regulation: (i) GR-DNA binding is facilitated, as revealed by dimethyl sulfate in vivo footprinting, leading to increased hormone-induced transcription, and (ii) the GR antagonist RU486 is converted into a partial agonist in the presence of FoxA1 via ligand-independent GR activation. We conclude that FoxA1 mediates a preset chromatin structure and directs a context-specific response of a nuclear receptor. Furthermore, the alternative nucleosome arrangement induced by GR and FoxA1 implies this to be determined by constitutive binding of transcription factors rather than by the DNA sequence itself.

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confidence: 51%

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confidence: 99%

FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter

Беликов

Åstrand

Wränge

2009

Molecular and Cellular Biology

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“…It has been demonstrated recently that GR and the Foxa family members Foxa1 and Foxa2 cooperate in transcription in organs such as prostate, mammary gland, and liver (35)(36)(37). Given the previously recognized role of Foxa3 in adipose tissues, we tested the hypothesis that Foxa3 could be involved in GR signaling and might facilitate GR function in fat.…”

Section: Resultsmentioning

confidence: 99%

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

Mueller

2016

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

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“…FoxA1 is a tissue-specific transcription factor that has the ability to bind and remodel compacted chromatin (Cirillo et al 2002;Holmqvist et al 2005). We noticed that FoxA1 was expressed in MCF7 (as well as in the other ER␣-positive breast cancer cell lines analyzed) and HepG2 but not in HeLa and MDA-MB-231 cells (Crowe et al 1999;Williamson et al 2005), paralleling the cellspecific functional activity of enh2.…”

Section: Functional Competency Of Enh2 Is Defined By Foxa1 and Is Crumentioning

confidence: 91%

A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer

Eeckhoute¹,

Carroll²,

Geistlinger³

et al. 2006

Genes Dev.

268

239

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Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor ␣ (ER␣) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ER␣ transcriptional mechanisms remains limited. Hence, it is still elusive why ER␣ ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ER␣ recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis-and trans-regulators of CCND1 expression where ER␣ collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC.[Keywords: Breast cancer; estrogen receptor; cyclin D1; transcription; enhancer; chromatin] Supplemental material is available at http://www.genesdev.org.

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FoxA1 binding to the MMTV LTR modulates chromatin structure and transcription

Cited by 35 publications

References 34 publications

FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter

FoxA1 Binding Directs Chromatin Structure and the Functional Response of a Glucocorticoid Receptor-Regulated Promoter

Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer

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