The Role of AP1 Family Members in Hormone Gene Expression

AP1 家族成员在激素基因表达中的作用

• 批准号: 9448100
• 负责人: DJURDJICA COSS
• 金额: $ 31.49万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9448100
• 关键词: Activins; Address; Affect; Age; Amenorrhea; Anterior Pituitary Gland; Binding; Biological; Blood Circulation; Cells; Complex; Couples; Data; Development; Dimerization; Disease; Enzymes; Epigenetic Process; Etiology; Event; Exhibits; FOXL2 gene; Failure; Family member; Female; Fertility; Follicle Stimulating Hormone; Functional disorder; Gametogenesis; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Gonadal structure; Gonadotrope Cell; Gonadotropin Hormone Releasing Hormone; Gonadotropins; HDAC3 gene; Hemorrhage; Heterodimerization; Histone Acetylation; Histone Deacetylase; Histones; Hormonal; Hormones; Hypothalamic structure; Immediate-Early Genes; In Vitro; Infertility; Investigation; Knockout Mice; Lead; Life; Luteinizing Hormone; Menopause; Menstrual cycle; Modeling; Molecular; NCOR1 gene; Ovarian; Ovary; Ovulation; Pathology; Periodicity; Phase; Phenotype; Physiologic pulse; Physiological; Physiology; Pituitary Gland; Play; Polycystic Ovary Syndrome; Postpartum Period; Precocious Puberty; Pregnancy; Premature Menopause; Premature Ovarian Failure; Prevalence; Production; Puberty; Regulation; Repression; Reproduction; Reproductive Physiology; Reproductive system; Role; Signal Pathway; Signal Transduction; Specificity; Steroid biosynthesis; Stimulus; Transcription Coactivator; Transcription Factor AP-1; Transcription Repressor/Corepressor; Transcriptional Regulation; Transgenic Mice; Wild Type Mouse; base; chromatin modification; chromatin remodeling; design; dimer; epigenetic regulation; fertility improvement; genome-wide; histone modification; hormone regulation; hypothalamic pituitary gonadal axis; in vivo; infertility treatment; inhibitor/antagonist; insight; knock-down; male; member; mouse model; novel; novel therapeutic intervention; premature; prevent; promoter; recruit; reproductive; reproductive fitness; reproductive function; response; statistics; transcription factor

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 α subunit and a unique β 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 FSHβ subunit expression via induction of cFos and cJun immediate early genes, which heterodimerize to form AP1 transcription factor. Increased FSHβ 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 FSHβ 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 FSHβ 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.

下丘脑-垂体-性腺（HPG）轴在哺乳动物生命的每个阶段都发挥着关键作用，包括青春期发育、月经周期、怀孕、产后和更年期。生育能力取决于该轴的精确荷尔蒙调节。两种最重要的激素，黄体生成素 (LH) 和卵泡刺激素 (FSH)，仅由垂体前叶的促性腺细胞产生。 LH 和 FSH 调节性腺生殖的关键方面，包括类固醇生成、配子发生和排卵。促性腺激素是常见 α 亚基和独特 β 亚基的异二聚体，具有生物特异性，是成熟激素合成的限制成分。它们的合成主要是为了响应下丘脑的促性腺激素释放激素 (GnRH)。此前，我们建立了基本机制并确定了调节促性腺激素基因表达的 GnRH 信号通路。我们确定 GnRH 通过诱导 cFos 和 cJun 立即早期基因来增加 FSHβ 亚基表达，这些基因异二聚化形成 AP1 转录因子。 FSHβ 表达增加导致循环中 FSH 水平升高，因为大部分 FSH 是组成型分泌的。利用充分表征的模型和迄今为止发展的理解，我们提出了三个新的目标，以弥合我们对体外和体内促性腺激素表达调节的理解上的差距，促性腺激素表达的功能障碍会导致不适当的激素水平和病理学。该提案重点关注基因表达和染色质修饰的表观遗传机制，这些机制在之前的研究中被忽视，但对于我们理解生育力的调节至关重要。根据初步数据，我们首先关注对限制促性腺激素水平和维持正常生殖功能至关重要的抑制因子，因为高水平的促性腺激素也会导致病理生理学。我们鉴定了 AP1 超家族的另一个成员 Jun 二聚蛋白 2 (JDP2)，它调节 FSHβ 亚基的表达。第一个目标是解决 JDP2 在体内的作用，特别是在垂体促性腺激素中的作用。该目标将分析 JDP2 的作用机制，作为一种新型转录抑制因子，它取代 cFos 作为 cJun 结合伴侣，从而对基因表达产生负面影响。第二个目标是分析组蛋白修饰酶组蛋白脱乙酰酶 3 (HDAC3) 在生殖功能中的作用，因为 HDAC3 是由 JDP2 招募的。第三个目标是确定与其表达相关的 FSHβ 基因的染色质重塑和组蛋白乙酰化。该目标侧重于通过转录抑制子和激活子招募共调节子和组蛋白修饰酶来调节的表观遗传变化。阐明有关促性腺激素基因表达的基本生理问题将有助于我们理解促性腺激素合成和分泌失调疾病（例如闭经、多囊卵巢综合征和卵巢早衰）的分子基础，并为设计新的治疗方法提供背景。