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Mechanisms and function of Tet1 regulated gene networks in intestinal stem cell biology

Tet1调控基因网络在肠道干细胞生物学中的机制和功能

基本信息

批准号：
9751284
负责人：
Adam David Gracz
金额：
$ 9.69万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-09 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751284
关键词：
Ablation Address Adult Alleles Animals Binding Sites Biological Assay Biological Markers Biology Cell Compartmentation Cell Proliferation Cell physiology Cells Cellular biology ChIP-seq Characteristics Chromatin Chromatin Structure Complex DNA DNA Modification Process Data Disease Elements Embryo Enzymes Exhibits Foundations Funding Future Gastrointestinal tract structure Gene Activation Gene Expression Profile Gene Expression Regulation Gene Family Genes Genetic Genetic Recombination Genetic Transcription Genome Genomics Goals Hematopoietic stem cells Homeostasis In Vitro Inflammation Intestines Life Mammals Maps Mediating Methodology Mitotic Modification Natural regeneration Neoplasms Organoids Physiology Play Polycomb Population Population Dynamics Property Regulation Regulator Genes Research Reserve Stem Cell Role Site Stem cells Structure Structure of intestinal gland Suggestion Testing Tissues Training Work base career cell type chromatin modification demethylation differential expression embryonic stem cell epigenomics functional outcomes gene repression gene translocation genome-wide histone modification in vivo interest intestinal epithelium intestinal homeostasis programs protein complex recruit repaired self-renewal skills stem cell biology stem cell differentiation stem cell population stemness transcriptome transcriptome sequencing

项目摘要

ABSTRACT Intestinal stem cells (ISCs) reside at the base of glandular structures, termed crypts, in the small intestinal epithelium. ISCs are defined by functional characteristics of self-renewal and multipotency, are thought to exist as multiple distinct populations, and exhibit remarkable plasticity during homeostasis as well in post-damage regeneration. The genetic regulation of this plasticity, especially in regards to myriad chromatin regulator elements, remains incompletely understood. At this career stage, my central goal is to supplement my expertise in ISC biology with new training in genomics in order to establish an independent career focused on chromatin regulation in ISCs. My preliminary data demonstrate that Tet1, which is a critical regulator DNA demethylation, is specifically upregulated in cell populations consistent with active and reserve ISCs. Additionally, subunits of the PRC2 complex, which is recruited to target sites by TET1, are differentially expressed between these two ISC populations. The central hypothesis of this study is that Tet1 establishes distinct gene regulatory networks in active and reserve ISCs. To test this hypothesis and meet my training goals, I will take a two-pronged approach to: (1) characterize the Tet1/PRC2 gene regulatory network by RNA- and ChIP-seq (Aims 1 and 2) and (2) apply these genome-scale findings to understanding functional outcomes in Tet1-null ISCs. This strategy will allow me to gain expertise in the experimental, conceptual, and practical approaches necessary to succeed in my independent career goals, as well as provide ample data to build a foundation for subsequent independent funding.

摘要