A systems biology approach to elucidating the frequency decoding mechanism governing differential mammalian gonadotropin-subunit gene expression

Abstract

The synthesis of the gonadotropin-subunits is directed by pulsatile gonadotropin-releasing hormone (GnRH) from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common alpha-subunit (aGSU), luteinizing hormone beta-subunit (LHb) and follicle-stimulating hormone beta-subunit (FSHb). In many vertebrate species, levels of these hormones vary quite dramatically throughout their life cycles owing to low levels of GnRH secretion that occur during the juvenile stage, suggesting a native state of gene repression. Preliminary findings point to the actions of histone deacetylases (HDACs) in repressing the gonadotropins. In this study, a system biology approach is taken to unravel the mechanisms for GnRH-frequency decoding and GnRH-induced de-repression of the gonadotropin-subunit genes. Three mitogen-activated protein kinases (MAPKs), ERK1/2, JNK and p38, are known to be contributing uniquely and combinatorially to the expression of each of these subunit genes. Using mathematical modeling and computer simulations, it was found that dual specificity phosphatase (DUSP) regulation of the activity of these MAPKs through negative feedback, forms the basis for decoding the frequency of pulsatile GnRH. Furthermore, a fourth MAPK, ERK5, whose activation kinetics and role in FSHb gene expression are shown, was found to enhance the preference of FSHb for low GnRH pulse frequencies. Evidence is presented for ERK5-activation of FSHb gene expression through Nur77-dependent and independent mechanisms, through interactions with MEF2D. This involves the Ca2+-activated calcineurin both in activating Nur77 transcription, as well as possibly dephosphorylating Nur77, which is required for its activity. Having established that distinct sets of HDACs repress the two beta-subunits, a role for GnRH-activated Ca2+/calmodulin-dependent protein kinase I (CaMKI) is elucidated in the de-repression of the FSHb gene, which primarily involves phosphorylating certain class IIa HDACs, critical for their nuclear export. Finally, Gem, a negative regulator of calcium L-type channels, is shown to be involved in regulating aGSU expression through influencing ERK1/2 activation in both a Ca2+-dependent and independent way.