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The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells.

Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA - Elife (2014)

Bottom Line: We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells.Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element.Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression.

View Article: PubMed Central - PubMed

Affiliation: Institut Jacques Monod, Paris, France.

ABSTRACT
FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.

No MeSH data available.


Related in: MedlinePlus

Characterization of estradiol transcriptional targets.(A) Heatmap of the expression values of genes modified >1.5-fold in the presence of E2. A bootstraped hierarchical clustering was performed on these genes, and the resulting tree is represented on the left. Five main clusters were obtained with 100% of support (3 clusters of E2-activated genes, 2 clusters of E2-repressed genes). (B) The left histograms display the average transcriptional effect of the indicated factor (FOXL2, E2, or E2 in the absence of FOXL2) within the indicated gene clusters. Error bars represent the SEM. Asterisks represent the p-value of a Student's t tests between the indicated conditions: ***p < 0.001; n.s.: non significant. The right graph displays the average variation of E2 transcriptional effect between the conditions where FOXL2 is present and the conditions where Foxl2 is knocked down, within the indicated clusters.DOI:http://dx.doi.org/10.7554/eLife.04207.018
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fig4s3: Characterization of estradiol transcriptional targets.(A) Heatmap of the expression values of genes modified >1.5-fold in the presence of E2. A bootstraped hierarchical clustering was performed on these genes, and the resulting tree is represented on the left. Five main clusters were obtained with 100% of support (3 clusters of E2-activated genes, 2 clusters of E2-repressed genes). (B) The left histograms display the average transcriptional effect of the indicated factor (FOXL2, E2, or E2 in the absence of FOXL2) within the indicated gene clusters. Error bars represent the SEM. Asterisks represent the p-value of a Student's t tests between the indicated conditions: ***p < 0.001; n.s.: non significant. The right graph displays the average variation of E2 transcriptional effect between the conditions where FOXL2 is present and the conditions where Foxl2 is knocked down, within the indicated clusters.DOI:http://dx.doi.org/10.7554/eLife.04207.018

Mentions: To have a broader view of the effect of FOXL2 on E2-induced transcriptional changes, we conducted an unsupervised hierarchical clustering of genes modified by >1.5-fold in the presence of E2 (Figure 4—figure supplement 3A). This analysis yielded three main groups of E2-activated genes and two groups of E2-repressed genes. These clusters were mainly characterized by the effect of the Foxl2 knockdown (Figure 4—figure supplement 3B). However, the average effect of E2 in the presence or absence of FOXL2 was remarkably similar between the groups. Indeed, E2 effect was reduced as much (≈40%) for FOXL2-repressed genes than for FOXL2-activated ones. This suggests an indirect effect of FOXL2 on E2-dependent transcriptional changes, that is, that FOXL2 is required for the expression of a mediator of E2-dependent transcriptional regulation. However, a direct cooperation or antagonism between FOXL2 and ERs may occur on some genes.


The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells.

Georges A, L'Hôte D, Todeschini AL, Auguste A, Legois B, Zider A, Veitia RA - Elife (2014)

Characterization of estradiol transcriptional targets.(A) Heatmap of the expression values of genes modified >1.5-fold in the presence of E2. A bootstraped hierarchical clustering was performed on these genes, and the resulting tree is represented on the left. Five main clusters were obtained with 100% of support (3 clusters of E2-activated genes, 2 clusters of E2-repressed genes). (B) The left histograms display the average transcriptional effect of the indicated factor (FOXL2, E2, or E2 in the absence of FOXL2) within the indicated gene clusters. Error bars represent the SEM. Asterisks represent the p-value of a Student's t tests between the indicated conditions: ***p < 0.001; n.s.: non significant. The right graph displays the average variation of E2 transcriptional effect between the conditions where FOXL2 is present and the conditions where Foxl2 is knocked down, within the indicated clusters.DOI:http://dx.doi.org/10.7554/eLife.04207.018
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4356143&req=5

fig4s3: Characterization of estradiol transcriptional targets.(A) Heatmap of the expression values of genes modified >1.5-fold in the presence of E2. A bootstraped hierarchical clustering was performed on these genes, and the resulting tree is represented on the left. Five main clusters were obtained with 100% of support (3 clusters of E2-activated genes, 2 clusters of E2-repressed genes). (B) The left histograms display the average transcriptional effect of the indicated factor (FOXL2, E2, or E2 in the absence of FOXL2) within the indicated gene clusters. Error bars represent the SEM. Asterisks represent the p-value of a Student's t tests between the indicated conditions: ***p < 0.001; n.s.: non significant. The right graph displays the average variation of E2 transcriptional effect between the conditions where FOXL2 is present and the conditions where Foxl2 is knocked down, within the indicated clusters.DOI:http://dx.doi.org/10.7554/eLife.04207.018
Mentions: To have a broader view of the effect of FOXL2 on E2-induced transcriptional changes, we conducted an unsupervised hierarchical clustering of genes modified by >1.5-fold in the presence of E2 (Figure 4—figure supplement 3A). This analysis yielded three main groups of E2-activated genes and two groups of E2-repressed genes. These clusters were mainly characterized by the effect of the Foxl2 knockdown (Figure 4—figure supplement 3B). However, the average effect of E2 in the presence or absence of FOXL2 was remarkably similar between the groups. Indeed, E2 effect was reduced as much (≈40%) for FOXL2-repressed genes than for FOXL2-activated ones. This suggests an indirect effect of FOXL2 on E2-dependent transcriptional changes, that is, that FOXL2 is required for the expression of a mediator of E2-dependent transcriptional regulation. However, a direct cooperation or antagonism between FOXL2 and ERs may occur on some genes.

Bottom Line: We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells.Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element.Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression.

View Article: PubMed Central - PubMed

Affiliation: Institut Jacques Monod, Paris, France.

ABSTRACT
FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.

No MeSH data available.


Related in: MedlinePlus