Foxl2 and Nr5a1 regulation in gonadotrope cells of the anterior pituitary
The mammalian reproductive system is regulated by gonadotrope cells in the anterior pituitary gland. These cells produce and secrete the gonadotropin hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH), responsible for germ cell maturation. Gonadotrope differentiation in the developing pituitary is driven by several transcription factors (TFs), among them FOXL2 and SF-1 (encoded by FOXL2 and NR5A1, respectively). FOXL2 and SF-1 also support mature gonadotrope function, notably expression of FSHB which encodes the FSH β-subunit. Despite their essential role in gonadotropes, little is known about how these factors are regulated in the pituitary. In this research, we aimed to find what regulates FOXL2 and NR5A1 in both differentiating and mature gonadotrope cells. We hypothesized that expression of both genes is activated by pituitary-specific factors and regulatory elements. We discovered, surprisingly, that activin A and GnRH, which both stimulate Fshb expression, repress Foxl2 and Nr5a1 expression in murine gonadotrope cells. Both Foxl2 and Nr5a1 have adjacent sequences transcribed to divergent long non-coding RNAs (lncRNAs), Foxl2os and Nr5a1os, that are co-expressed in a tissue-specific manner and respond to the same stimulus as the protein coding genes. Of these lncRNAs, Foxl2os shows potential as a Foxl2 regulator, possibly through the formation of G-quadruplexes and iMotifs that we detected and appear to impact Foxl2os levels. Additionaly, using published ATAC-seq data, we have identified a putative gonadotrope specific super-enhancer upstream of the Foxl2 promoter. Targeting dCas9-KRAB to this region reduced Foxl2 mRNA levels, indicating a functional role. This function is supported by the presence of annotated ChIP-seq binding of TFs that are expressed in differentiating pre-gonadotropes prior to Foxl2. These results offer novel candidates for the regulation of two genes crucial for human fertility.
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