Deciphering the gene regulatory network controlling vertebrate endodermal fates

破译控制脊椎动物内胚层命运的基因调控网络

• 批准号: 9256494
• 负责人: Ken W.Y. Cho
• 金额: $ 56.04万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256494
• 关键词: Adult; Binding; Bioinformatics; Biological Models; Biology; Cell Lineage; ChIP-seq; Collaborations; Communities; Complex; Computer Simulation; Coupled; DNA Binding; DNA sequencing; DNase I hypersensitive sites sequencing; Data; Data Set; Development; Developmental Process; Ectoderm; Embryo; Embryonic Development; Endoderm; Endoderm Cell; Engineering; Feeds; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomics; Germ Layers; Goals; Graph; High-Throughput Nucleotide Sequencing; Human; Intestines; Knowledge; Liver; Logic; Lung; Measurement; Measures; Mediating; Mesoderm; Methods; Modeling; Molecular; Molecular Profiling; Mus; NIH Program Announcements; Organ; Organogenesis; Output; Pancreas; Pathway interactions; Pattern; Play; Production; RNA; Rana; Regulator Genes; Research; Research Personnel; Stem cells; Surveys; System; Testing; Thyroid Gland; Time; Translating; Tube; United States National Institutes of Health; Xenopus; cell type; computerized tools; epigenomics; feeding; gastrulation; genome-wide; human data; human disease; human stem cells; human tissue; insight; knock-down; model building; network models; outcome prediction; programs; public health relevance; skills; stem cell biology; tool; transcription factor; transcriptome sequencing; vertebrate embryos; vertebrate genome

DESCRIPTION (provided by applicant): Many human diseases are associated with organs originating from the embryonic gut tube, including the intestine, pancreas, liver, lungs, and thyroid. So far, only a handful of transcription factors (TFs) are known to play key roles in endoderm development, and how these TFs functionally interact in a gene regulatory network (GRN) is poorly understood and the extent to which they modulate endoderm patterning and early organogenesis is unknown. Large-scale genomic analyses are needed to generate a GRN with predictive power and to gain a systems-level understanding of the regulatory logic controlling endoderm development. We propose to utilize the experimental advantages of the Xenopus embryo coupled with several high- throughput sequencing methods to survey the global landscape of cis-regulatory modules (CRMs) active in the early Xenopus embryo and use these datasets to build and to analyze an endoderm GRN that is robust enough to be predictive when perturbed. Our modeling will provide testable hypotheses for performing double knockdowns to test the predictive quality of our GRN and to reveal the importance of multifactorial control over endodermal genes. Double knockdowns are difficult to perform in developing mammalian embryos, but are straightforward in Xenopus. This results in further elaboration of the GRN and yields deeper insights into gene regulation, which is not possible by performing additional single gene knockdown studies. We will compare our resulting GRNs in Xenopus to human data and identify critical network interactions that can be manipulated to engineer endodermal tissues from human stem cells. Our specific aims are: Aim 1: Generate genome-wide datasets of the inputs and outputs of transcriptional networks in order to build an endodermal GRN. Aim 2: Computationally integrate ChIP-seq, DNA-seq, and RNA-seq across a developmental time course to build an embryonic interactome graph. Aim 3: Model an endodermal GRN, make predictions that identify critical nodes, and test the model. This project will generate a predictive GRN model with an unprecedented systems level view of endoderm development in the vertebrate embryo. This will have a significant impact on our understanding of germ layer formation and how GRNs coordinate embryogenesis. Our GRN models will have an impact beyond the Xenopus community because researchers studying mammalian development and stem cell biology will derive testable hypotheses to drive their research programs. Similarly, the tools developed in this proposal will be applicable to building GRNs for other vertebrate and mammalian systems.

项目成果

Biallelic genome modification in F(0) Xenopus tropicalis embryos using the CRISPR/Cas system.

• DOI: 10.1002/dvg.22719
• 发表时间: 2013-12
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Blitz, Ira L.;Biesinger, Jacob;Xie, Xiaohui;Cho, Ken W. Y.
• 通讯作者: Cho, Ken W. Y.

Early Xenopus gene regulatory programs, chromatin states, and the role of maternal transcription factors.

• DOI: 10.1016/bs.ctdb.2020.02.009
• 发表时间: 2020
• 期刊: Current topics in developmental biology
• 作者: Kitt D. Paraiso;J. Cho;Junseok Yong;Ken W. Y. Cho

Prospects for Declarative Mathematical Modeling of Complex Biological Systems.

复杂生物系统声明式数学建模的前景。

• DOI: 10.1007/s11538-019-00628-7
• 发表时间: 2019
• 期刊: Bulletin of mathematical biology
• 影响因子: 3.5
• 作者: Mjolsness,Eric

Occupancy of tissue-specific cis-regulatory modules by Otx2 and TLE/Groucho for embryonic head specification.

• DOI: 10.1038/ncomms5322
• 发表时间: 2014-07-09
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Yasuoka Y;Suzuki Y;Takahashi S;Someya H;Sudou N;Haramoto Y;Cho KW;Asashima M;Sugano S;Taira M
• 通讯作者: Taira M

DNase-seq to Study Chromatin Accessibility in Early Xenopus tropicalis Embryos.

• DOI: 10.1101/pdb.prot098335
• 发表时间: 2019-04-01
• 期刊: Cold Spring Harbor protocols
• 作者: Cho, Jin Sun;Blitz, Ira L;Cho, Ken W Y
• 通讯作者: Cho, Ken W Y