Novel enhancers in transcriptional regulation of the gonadotropin genes
The pituitary gland luteinizing hormone (LH) and follicle stimulating hormone (FSH) control gonadal development and function, their levels changing dramatically at puberty, during the estrous/menstrual cycle and at menopause, in response to complex hormonal signals. We hypothesized that distal DNA elements regulate Lhb and Fshb expression to mediate some of these effects. We identified a bi-directional enhancer and lncRNA which play distinct and sex-specific roles in Lhb expression, and found that both elements are regulated by non-canonical DNA structures. Far upstream of Fshb, we detected a gonadotrope-specific “super-enhancer” whose activity affects Fshb mRNA levels. Protein binding and transcription of this region increased in response to activin, and the transcription increased in a mouse model of menopause which is characterized by high levels of activin activity. This indicates a role for the region in mediating the elevation of FSH at menopause, which underlies the onset of several age-related diseases. Our findings reveal novel mechanisms involved in control of the reproductive axis, and shed new light on transcriptional regulation via various distal non-coding genomic elements.
