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: 9765346
• 负责人: DJURDJICA COSS
• 金额: $ 31.46万
• 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/9765346
• 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; Ovarian Hyperstimulation Syndrome; 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 - 辅助（HPG）轴在哺乳动物生活的每个阶段都起着关键作用，包括青春期发育，月经周期，怀孕，产后和绝经。生育能力取决于该轴的精确调节。两种最关键的骑马，是叶酸马酮（LH）和刺激叶的骑马（FSH），仅在前垂体的促性腺细胞中生产。 LH和FSH调节性腺繁殖的关键方面，包括类固醇生成，配子发生和排卵。促性腺激素骑马是常见α亚基和独特的β亚基的异二聚体，该亚基提供了生物学特异性，并且是成熟骑马合成的限制成分。它们主要是根据下丘脑释放促性腺激素释放雌激素（GNRH）的。以前，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通过立即诱导CFO和CJUN的早期基因来增加FSHβ亚基的表达，这些基因杂二聚二聚体形成AP1转录因子。由于大多数FSH始终分泌，FSHβ表达增加会导致循环中较高的FSH水平。利用特征良好的模型以及到目前为止发展的理解，我们提出了三个新颖的旨在弥合对体外和体内促性腺激素表达的调节的差距，从而导致适当的骑马水平和病理学的功能障碍。该提案的重点是在先前研究中忽略的基因表达和染色质修饰的表观遗传机制，但对于我们理解对生育能力的调节至关重要。基于初步数据，我们首先关注的反射器至关重要的反射剂，以限制促性腺激素的水平并保持正常的生殖功能，因为高水平的促性腺激素也会导致病理生理。我们确定了AP1超家族的附加成员，即Jun Dimerization蛋白2（JDP2），该蛋白2（JDP2）调节FSHβ亚基的表达。第一个目的是针对JDP2在体内的作用，特别是在垂体性促性腺肿瘤中。该目标将分析JDP2作用机理，作为一种新型的转录复制品，将CFO置换为CJUN结合伴侣，从而对基因表达产生负面影响。第二个目标将分析组蛋白修饰酶，组蛋白脱乙酰基酶3（HDAC3）在生殖功能中的作用，因为HDAC3由JDP2募集。第三个目标将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。该目标重点是通过募集组蛋白和转录激活因子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的疾病的分子基础，例如闭经，多囊性卵巢综合征和早期卵巢衰竭，并为新颖的方法提供了新型疗效方法的背景。