Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin

The genes encoding luteinizing hormone and follicle stimulating hormone are activated by gonadotropin-releasing hormone (GnRH), and we hypothesized that this involves GnRH-induction of various histone modifications. At basal conditions in an immature gonadotrope-derived cell line, the hormone-specific β-subunit gene promoters are densely packed with histones, and contain low levels of H3K4 trimethylation (H3K4me3). GnRH both induces this modification and causes histone loss, creating a more active chromatin state. The H3K4me3 appears to be mediated by menin and possibly catalyzed by the menin-mixed-lineage leukemia (MLL) 1/2 methyl transferase complex, as inhibition of MLL recruitment or menin knockdown reduced gene expression and the levels of H3K4me3 on all three promoters. Menin recruitment to the β-subunit gene promoters is increased by GnRH, possibly involving transcription factors such as estrogen receptor α and/or steroidogenic factor 1, with which menin interacts. Menin also interacts with ring finger protein 20, which ubiquitylates H2BK120 (H2BK120ub), which was reported to be a pre-requisite for H3K4me3 at various gene promoters. Although levels of H2BK120ub are increased by GnRH in the coding regions of these genes, levels at the promoters do not correlate with those of H3K4me3, nor with gene expression, suggesting that H3K4me3 is not coupled to H2BK120ub in transcriptional activation of these genes.