Transcriptional regulatory networks govering placental development.

控制胎盘发育的转录调控网络。

基本信息

批准号：
10406355
负责人：
Geetu Tuteja
金额：
$ 29.87万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-24 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406355
关键词：
ATAC-seq Adult Binding Binding Sites Biological Assay Cell Line Cells Cessation of life ChIP-seq Complex Computer Analysis Data Decidua Development Disease Early Diagnosis Early treatment Embryo Enhancers Ensure Fetal Growth Retardation Fetus Gene Abnormality Gene Expression Genes Genetic Genetic Transcription Genomic DNA Genomics Goals Growth Human Knowledge Lead Metabolic Methods Mission Mothers Mus National Institute of Child Health and Human Development Nucleic Acid Regulatory Sequences Nutrient Outcome Pathogenesis Pathology Pathway interactions Placenta Placenta Diseases Placentation Pre-Eclampsia Pregnancy Pregnancy Complications Pregnancy Outcome Process Public Health Publishing Regulation Reporter Research Small Interfering RNA Syncytiotrophoblast Testing Therapeutic Intervention Time Tissues Variant Work adverse pregnancy outcome base biomarker development cell motility computerized tools computing resources early onset genome-wide genomic RNA innovation knock-down knockout gene member migration neonatal death novel marker novel therapeutic intervention prevent spatiotemporal stillbirth tool transcription factor transcription regulatory network transcriptome sequencing trophoblast

项目摘要

Abnormal gene expression during early placental development has been associated with adverse pregnancy outcomes. However, the transcriptional regulatory networks underlying normal placental development, includ- ing the transcription factors, the enhancers they bind to, and the genes they regulate, are unknown. Until this fundamental gap is filled, the variants in genomic DNA that cause aberrant gene expression and lead to preg- nancy complications cannot be understood. The applicant’s long-term goal is to identify global mechanisms by which transcription factors and enhancers work together to regulate placental development. The overall objec- tive of this application is to define and characterize transcriptional regulatory networks for processes that occur during three critical time points of mouse placental development (embryonic days 7.5, 8.5, and 9.5), prior to the formation of the mature placenta. The central hypothesis, based on published and preliminary data, is that time point-specific transcriptional regulatory networks regulate distinct processes during early placental develop- ment, and that disruption of transcription factors or enhancers central to these networks leads to abnormal trophoblast gene expression. The rationale for the proposed research is that understanding the regulatory net- works underlying early placental development will enable early detection and treatment of placental disorders. The central hypothesis will be tested using three specific aims: (1) to define process-specific transcriptional regulatory networks during early placental development;; (2) to determine the mechanisms by which key TF- enhancer pairs regulate gene expression in mouse trophoblast subtypes;; and (3) to determine the relationship between cis-regulation in mouse and human trophoblasts. To execute these aims, we will use an integrated approach, combining experimental genomics (RNA-Seq, ChIP-Seq, and ATAC-Seq), computational analysis (e.g. co-expression analysis, enhancer module analysis, and binding site predictions), and functional assays (e.g. ChIP, reporter assays, and siRNA knockdown). Each aim is supported by a strong scientific premise and preliminary data, and each method has been established either in the applicant’s lab or in the lab of a member of the research team. Completion of this project will result in a global understanding of the transcriptional net- works regulating early placental development, and in an understanding of the mechanisms by which key TF- enhancer pairs regulate gene expression in mouse and human trophoblast cells. The research proposed in this application is innovative, in the applicant’s opinion, because it represents a new and substantive departure from the status quo by shifting focus to genome-scale identification and characterization of TF-enhancer net- works that regulate specific processes during placental development. This contribution is significant because it will provide a new understanding of normal placental development, ultimately leading to the development of novel therapeutic interventions for placenta-associated disorders.

早期发育期间基因表达异常与不良妊娠有关结果。但是，正常占地发展的基础的转录调节网络，包括 - 转录因子，与它们结合的增强子以及调节的基因是未知的。在填补了这个基本差距之前，基因组DNA中引起异常基因表达并导致预先进行的变体南希并发症无法理解。申请人的长期目标是通过哪些转录因子和增强剂共同调节位置发育。总体objec- 该应用程序的构成是定义和表征ocur的过程的转录调节网络在小鼠位置发育的三个关键时间点（胚胎天7.5、8.5和9.5），之前成熟plapeta的形成。基于已发布和初步数据的中心假设是特定于点的转录调节网络在早期发展期间调节不同的过程 - 这些网络中心的转录因子或增强子的破坏导致异常滋养细胞基因表达。拟议研究的理由是了解监管网络早期占地开发的基础作品将能够早期检测和治疗斑点疾病。中央假设将使用三个特定目的测试：（1）定义特定过程转录。早期开发期间的监管网络；（2）确定关键TF-的机制增强子对调节小鼠滋养细胞亚型中的基因表达；（3）确定关系在小鼠和人类滋养细胞中的顺式调节之间。为了执行这些目标，我们将使用集成的方法，结合实验基因组学（RNA-SEQ，CHIP-SEQ和ATAC-SEQ），计算分析（例如共表达分析，增强子模块分析和结合位点预测）和功能测定（例如，芯片，记者测定法和sirna注意）。每个目标都得到了强大的科学前提的支持，初步数据，每种方法已在申请人的实验室或成员的实验室中建立研究团队。该项目的完成将导致全球对转录网络的了解调节早期占地发展的作品，并了解关键TF-的机制增强子对调节小鼠和人滋养细胞细胞中的基因表达。这项研究提出了在应用程序的意见中，应用是创新的，因为它代表了一个新的和实质性的出发从将重点转移到基因组规模的识别和TF-增强器网络的表征和表征调节位置开发过程中特定过程的作品。这项贡献很重要，因为它将对正常的占地发展提供新的理解，最终导致新型的治疗干预措施，用于与放和相关的疾病。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PlacentaCellEnrich: A tool to characterize gene sets using placenta cell-specific gene enrichment analysis.

DOI：
10.1016/j.placenta.2020.10.029
发表时间：
2021-01-01
期刊：
Placenta
影响因子：
3.8
作者：
Jain A;Tuteja G
通讯作者：
Tuteja G

Unsupervised Contrastive Peak Caller for ATAC-seq.

用于 ATAC-seq 的无监督对比峰值调用器。

DOI：
10.1101/2023.01.07.523108
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Vu,HaTH;Zhang,Yudi;Tuteja,Geetu;Dorman,Karin
通讯作者：
Dorman,Karin

Identifying novel regulators of placental development using time-series transcriptome data.

DOI：
10.26508/lsa.202201788
发表时间：
2023-02
期刊：
Life science alliance
影响因子：
4.4
作者：
通讯作者：

The product of BMP-directed differentiation protocols for human primed pluripotent stem cells is placental trophoblast and not amnion.

DOI：
10.1016/j.stemcr.2022.04.014
发表时间：
2022-06-14
期刊：
STEM CELL REPORTS
影响因子：
5.9
作者：
Seetharam, Arun S.;Vu, Ha T. H.;Choi, Sehee;Khan, Teka;Sheridan, Megan A.;Ezashi, Toshihiko;Roberts, R. Michael;Tuteja, Geetu
通讯作者：
Tuteja, Geetu

The impact of bisphenol A on the placenta†.