Transcriptomic and epigenomic basis for reproductive dysfunction during stress

应激期间生殖功能障碍的转录组和表观基因组基础

基本信息

项目摘要

Project Summary/Abstract Stress is considered a major factor in the development of menstrual cycle disorders, amenorrhea, and infertility, affecting 25% of reproductive age women. To date, the neuroendocrine causes of stress-induced infertility are not completely understood. Enhanced secretion of glucocorticoids (CORT) is a common and critical response to all stressors. We demonstrated that a stress level of CORT disrupts the ovulatory cycle of female mice via suppression of kisspeptin (Kiss1) neurons located in both arcuate (ARCKiss1) and anteroventral periventricular (AVPVKiss1) nuclei, which are essential components of the neural control of reproduction. The effect of CORT depends on ovarian steroid milieu. Specifically, low diestrus levels of estradiol enable CORT to impair ARCKiss1 control of luteinizing hormone (LH) pulses and high surge estradiol levels enable CORT to prevent AVPVKiss1 neuronal activation of the LH secretion. Receptors for estrogen and glucocorticoid receptors (GR) are both in Kiss1 neurons; however, the interaction of GR and ER to modulate the transcriptomic and epigenomic landscape within ARCKiss1 or AVPVKiss1 neurons to suppress LH secretion remains unclear. This proposal employs a cutting- edge method to capture and isolate Kiss1 cells from heterogeneous ARC or AVPV cell populations. The Isolation of Nuclei Tagged in specific Cell-Types (INTACT) protocol employs expression of a tagged nuclear envelope protein (Sun1) only in Kiss1 cells (i.e. Cre-dependent) for rapid isolation of tagged nuclei for downstream transcriptomic and epigenomic sequencing. Aim 1 will test the hypothesis that estradiol enables CORT to alter the transcriptome of Kiss1 neurons, facilitating suppressed ARCKiss1 and AVPVKiss1 neuronal activity and lowered pulsatile and surge-type LH secretion, respectively. Mice will be OVX and receive diestrus-like (ARCKiss1) or surge-level replacement (AVPVKiss1) of estradiol and treated with CORT or cholesterol (control), and the transcriptome of INTACT-isolated Kiss cells will be evaluated by RNA-sequencing. Aim 2 will test the hypothesis that estradiol drives changes of the chromatin landscape of ARCKiss1 and AVPVKiss1 neurons allowing GR to bind and alter the neuronal transcriptome. INTACT will be coupled with: (2.1) Assay for Transposase-Accessible Chromatin (ATAC-seq) to evaluate the epigenome for open chromatin in mediated by estradiol and CORT and (2.2) chromatin immunoprecipitation (ChIP-seq) to directly map the genome-wide binding profile of GR in ARCKiss1 and AVPVKiss1 cells to test the hypothesis that GR binding sites are made accessible by estradiol (hormone treatments described in Aim 1). Successful completion of this proposal will significantly increase our knowledge of intracellular mechanisms that govern the physiologic responsiveness of Kiss1 neurons, which will be tested in subsequent work and may identify druggable targets to influence the management of reproductive disorders resulting from impaired central regulation. This application falls within the scope of the high risk-high reward mechanism and will result in novel reagents that will impact biomedical research. All methods, hormone treatments and the animal model (Kiss1-CrexSun1-GFP) are available within this investigative team.
项目总结/摘要 压力被认为是月经周期紊乱、闭经和不孕的主要因素, 影响了25%的育龄妇女。到目前为止,神经内分泌的原因,压力引起的不孕症是 不完全理解。糖皮质激素分泌增强(CORT)是一种常见的和关键的反应, 所有压力源我们证明应激水平的CORT通过以下途径破坏雌性小鼠的排卵周期: 抑制位于弓状(ARCKiss 1)和前腹侧脑室周围的kisspeptin(Kiss 1)神经元 (AVPVKiss 1)核,这是生殖神经控制的重要组成部分。CORT的作用 取决于卵巢类固醇环境特别是,动情间期低水平的雌二醇使CORT损害ARCKiss 1 控制促黄体生成激素(LH)脉冲和高雌二醇水平使CORT能够预防AVPVKiss 1 LH分泌的神经元激活。雌激素受体和糖皮质激素受体(GR)都在 Kiss 1神经元;然而,GR和ER的相互作用调节转录组和表观基因组景观 在ARCKiss 1或AVPVKiss 1神经元内抑制LH分泌的机制尚不清楚。该提案采用了一种切割- 边缘方法从异质ARC或AVPV细胞群中捕获和分离Kiss 1细胞。隔离 在特定细胞类型中标记的细胞核的表达(INTACT)方案采用标记的核膜的表达 蛋白(Sun 1)仅在Kiss 1细胞(即Cre依赖性)中用于快速分离标记的细胞核,用于下游 转录组和表观基因组测序。目的1将检验雌二醇使CORT改变的假设, Kiss 1神经元的转录组,促进ARCKiss 1和AVPVKiss 1神经元活性的抑制, 脉冲型和浪涌型LH分泌。小鼠将进行OVX并接受间情期样(ARCKiss 1)或 雌二醇的峰水平替代(AVPVKiss 1),并用CORT或胆固醇(对照)治疗, 将通过RNA测序评价INTACT分离的Kiss细胞的转录组。目标2将检验假设 雌二醇驱动ARCKiss 1和AVPVKiss 1神经元染色质景观的变化,允许GR结合 并改变神经元的转录组INTACT将结合:(2.1)转座酶可降解性测定 染色质(ATAC-seq),以评估雌二醇和CORT介导的开放染色质的表观基因组, (2.2)染色质免疫沉淀(ChIP-seq)直接映射GR的全基因组结合谱, ARCKiss 1和AVPVKiss 1细胞,以检验GR结合位点可被雌二醇接近的假设 (目标1中描述的激素治疗)。成功完成这一提案将大大提高我们的 了解控制Kiss 1神经元生理反应的细胞内机制, 在随后的工作中进行测试,并可能确定影响生殖管理的药物靶点。 由于中枢调节受损而引起的紊乱。此应用程序福尔斯高风险-高 奖励机制,并将导致新的试剂,将影响生物医学研究。所有方法,激素 治疗和动物模型(Kiss 1-CrexSun 1-GFP)在该研究小组内可用。

项目成果

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KELLIE Breen Church其他文献

KELLIE Breen Church的其他文献

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{{ truncateString('KELLIE Breen Church', 18)}}的其他基金

FASEB SRC: The Mechanisms of Allostasis Conference: Stressed or Stressed Out
FASEB SRC:动态平衡机制会议:压力还是压力过大
  • 批准号:
    10537130
  • 财政年份:
    2022
  • 资助金额:
    $ 23.69万
  • 项目类别:
Transcriptomic and epigenomic basis for reproductive dysfunction during stress
应激期间生殖功能障碍的转录组和表观基因组基础
  • 批准号:
    10394958
  • 财政年份:
    2021
  • 资助金额:
    $ 23.69万
  • 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
  • 批准号:
    10298510
  • 财政年份:
    2021
  • 资助金额:
    $ 23.69万
  • 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
  • 批准号:
    10684307
  • 财政年份:
    2021
  • 资助金额:
    $ 23.69万
  • 项目类别:
Regulation of gonadotropin secretion during undernutrition by a brainstem-hypothalamic neural pathway
脑干-下丘脑神经通路对营养不良期间促性腺激素分泌的调节
  • 批准号:
    10488654
  • 财政年份:
    2021
  • 资助金额:
    $ 23.69万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9325553
  • 财政年份:
    2016
  • 资助金额:
    $ 23.69万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9895818
  • 财政年份:
    2016
  • 资助金额:
    $ 23.69万
  • 项目类别:
Neuroendocrine Regulation of Reproduction by Glucocorticoids
糖皮质激素对生殖的神经内分泌调节
  • 批准号:
    9177432
  • 财政年份:
    2016
  • 资助金额:
    $ 23.69万
  • 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
  • 批准号:
    7893551
  • 财政年份:
    2010
  • 资助金额:
    $ 23.69万
  • 项目类别:
The Role of Gonadotrope in Stress-Induced Reproductive Impairment
促性腺激素在压力引起的生殖损伤中的作用
  • 批准号:
    8810674
  • 财政年份:
    2010
  • 资助金额:
    $ 23.69万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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