The hypothalamic-pituitary-gonadal (HPG) axis plays a pivotal role in every phase of mammalian life, including pubertal development, the menstrual cycle, pregnancy, postpartum, and menopause. Fertility depends on precise hormonal regulation of this axis. Two of the most critical hormones, luteinizing hormone (LH) and follicle- stimulating hormone (FSH), are produced exclusively in the gonadotrope cells of the anterior pituitary. LH and FSH regulate crucial aspects of reproduction in the gonads, including steroidogenesis, gametogenesis, and ovulation. Gonadotropin hormones are heterodimers of a common ? subunit and a unique ? subunit, which provides biological specificity and is a limiting component of the mature hormone synthesis. They are synthesized primarily in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. Previously, we established fundamental mechanisms and identified GnRH signaling pathways that regulate gonadotropin gene expression. We determined that GnRH increases FSH? subunit expression via induction of cFos and cJun immediate early genes, which heterodimerize to form AP1 transcription factor. Increased FSH? expression results in higher FSH levels in the circulation since the majority of FSH is constitutively secreted. Taking advantage of well-characterized models and the understanding developed thus far, we propose three novel aims to bridge a gap in our understanding of the regulation of gonadotropin expression in vitro and in vivo, dysfunction of which results in inappropriate hormone levels and pathology. This proposal focuses on epigenetic mechanisms of gene expression and chromatin modifications that have been overlooked in previous investigations, but are critical for our understanding of regulation of fertility. Based on preliminary data, we first focus on repressors critical to constrain gonadotropin hormone levels and maintain normal reproductive function, since high levels of gonadotropins also lead to pathophysiology. We identified an additional member of AP1 superfamily, Jun Dimerization Protein 2 (JDP2), which regulates the expression of the FSH? subunit.
The first aim addresses the role of JDP2 in vivo, particularly in the pituitary gonadotrope.
This aim will analyze JDP2 mechanism of action, as a novel transcriptional repressor that displaces cFos as a cJun binding partner, thereby negatively impacting gene expression.
The second aim will analyze the role of histone modification enzyme, histone deacetylase 3 (HDAC3) in reproductive function since HDAC3 is recruited by JDP2.
The third aim will determine chromatin remodeling and histone acetylation of the FSH? gene that correlate with its expression.
This aim focuses on epigenetic changes regulated by recruitment of coregulators and histone modifying enzymes by repressors and activators of transcription. Elucidating fundamental physiological questions regarding gene expression in the gonadotrope will contribute to our understanding of the molecular basis of disorders with dysregulated gonadotropin synthesis and secretion, such as amenorrhea, polycystic ovary syndrome and premature ovarian failure, and provide a context for the design of novel therapeutic approaches.
Precise fluctuation and rhythmic expression of gonadotropin hormones, governed by the pulses of hypothalamic GnRH, are crucial for normal reproductive capacity and survival of the species. This proposal addresses the role of a transcriptional repressor and chromatin remodeling in the gonadotrope, which may serve as a switch between induction of expression and gene silencing, but has been overlooked in previous studies. Understanding the molecular mechanisms whereby gonadotropes can positively and negatively respond to hypothalamic signals will provide insight into the physiology and pathophysiology of the mammalian reproductive system as a whole.
