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FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression

View Article: PubMed Central - PubMed

ABSTRACT

Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2, and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. ChIP-seq analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not re-programs, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer.

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A model depicting the hierarchical regulatory network of FOXA1, GATA2, and ARFOXA1 acts up-stream to GATA2 and AR by functioning as a pioneer factor that defines and reprograms both GATA2 and AR cistromes. By contrast, GATA2 and AR are co-activators of each other, which also potentiate, but do not reprogram, FOXA1 binding to chromatin. Our study reveal distinct molecular mechanisms by which FOXA1 and GATA2 regulate AR cistrome and suggest a unique, reprogramming, role of FOXA1 that is central to hormonal regulation of gene expression in prostate cancer.
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Figure 7: A model depicting the hierarchical regulatory network of FOXA1, GATA2, and ARFOXA1 acts up-stream to GATA2 and AR by functioning as a pioneer factor that defines and reprograms both GATA2 and AR cistromes. By contrast, GATA2 and AR are co-activators of each other, which also potentiate, but do not reprogram, FOXA1 binding to chromatin. Our study reveal distinct molecular mechanisms by which FOXA1 and GATA2 regulate AR cistrome and suggest a unique, reprogramming, role of FOXA1 that is central to hormonal regulation of gene expression in prostate cancer.

Mentions: In summary, the robust reprogramming ability shown by FOXA1, but not GATA2, suggests an interesting model wherein FOXA1 resides at the top of a hierarchical network of transcription factors that control AR cistrome (Figure 7). FOXA1 defines AR and GATA2 binding sites, which, on the other hand, further enhance FOXA1 chromatin occupancy, forming a positive feedback loop. By contrast, GATA2 is not able to define/reprogram AR cistrome but acts as a strong co-activator that positively regulate AR expression as well as potentiate AR binding on the chromatin. Consequently, GATA2 is a clear inducer of AR-mediated gene expression program, while FOXA1 exhibits context-dependent roles in its regulation of GATA2 and AR downstream pathways. Therefore, our studies provide an innovative model wherein we show for the first time the different mechanisms involved in FOXA1 and GATA2 regulation of AR cistrome and suggest that FOXA1 acts upstream of GATA2, and potential many other AR co-activators, in defining AR cistrome and determining AR-mediated transcriptional program in prostate cancer.


FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression
A model depicting the hierarchical regulatory network of FOXA1, GATA2, and ARFOXA1 acts up-stream to GATA2 and AR by functioning as a pioneer factor that defines and reprograms both GATA2 and AR cistromes. By contrast, GATA2 and AR are co-activators of each other, which also potentiate, but do not reprogram, FOXA1 binding to chromatin. Our study reveal distinct molecular mechanisms by which FOXA1 and GATA2 regulate AR cistrome and suggest a unique, reprogramming, role of FOXA1 that is central to hormonal regulation of gene expression in prostate cancer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940300&req=5

Figure 7: A model depicting the hierarchical regulatory network of FOXA1, GATA2, and ARFOXA1 acts up-stream to GATA2 and AR by functioning as a pioneer factor that defines and reprograms both GATA2 and AR cistromes. By contrast, GATA2 and AR are co-activators of each other, which also potentiate, but do not reprogram, FOXA1 binding to chromatin. Our study reveal distinct molecular mechanisms by which FOXA1 and GATA2 regulate AR cistrome and suggest a unique, reprogramming, role of FOXA1 that is central to hormonal regulation of gene expression in prostate cancer.
Mentions: In summary, the robust reprogramming ability shown by FOXA1, but not GATA2, suggests an interesting model wherein FOXA1 resides at the top of a hierarchical network of transcription factors that control AR cistrome (Figure 7). FOXA1 defines AR and GATA2 binding sites, which, on the other hand, further enhance FOXA1 chromatin occupancy, forming a positive feedback loop. By contrast, GATA2 is not able to define/reprogram AR cistrome but acts as a strong co-activator that positively regulate AR expression as well as potentiate AR binding on the chromatin. Consequently, GATA2 is a clear inducer of AR-mediated gene expression program, while FOXA1 exhibits context-dependent roles in its regulation of GATA2 and AR downstream pathways. Therefore, our studies provide an innovative model wherein we show for the first time the different mechanisms involved in FOXA1 and GATA2 regulation of AR cistrome and suggest that FOXA1 acts upstream of GATA2, and potential many other AR co-activators, in defining AR cistrome and determining AR-mediated transcriptional program in prostate cancer.

View Article: PubMed Central - PubMed

ABSTRACT

Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2, and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. ChIP-seq analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not re-programs, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer.

No MeSH data available.


Related in: MedlinePlus