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Molecular functions of Tcf-1 in DP thymocytes

DP胸腺细胞中Tcf-1的分子功能

基本信息

批准号：
10617463
负责人：
Fotini Gounari
金额：
$ 21.22万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-22 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10617463
关键词：
3-Dimensional Address Binding Binding Proteins Binding Sites CD8B1 gene Cell Lineage Cell Proliferation Cells Chromatin Chromatin Structure Complex DNA DNA Binding DNA Binding Domain DNA Sequence DNA-Binding Proteins Data Development Developmental Process Differentiated Gene Disease E-Box Elements Enhancers Epigenetic Process Eukaryota Event Family Gene Activation Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Immune Immunity Individual Internet Knowledge Length Literature Mediating Molecular Molecular Conformation Mus Mutate Nuclear Outcome Process Promoter Regions Protein Isoforms Proteins Regulation Regulatory Element Research Role Series Shapes Site T cell differentiation T cell transcription factor 1 T-Cell Development T-Lymphocyte Testing Therapeutic Intervention Thymocyte Development Thymus Gland Tissues Tumor stage base beta catenin cdc Genes gene repression genetic regulatory protein genome-wide lymphoid enhancer-binding factor 1 member molecular modeling novel operation programs promoter protein complex recruit thymocyte

项目摘要

PROJECT SUMMARY Thymic development is highly responsible for shaping a healthy and balanced T cell immunity. Like other developmental processes it involves coordinated changes in the linear and three-dimensional chromatin organization that allow stage specific transcription events. A central regulator at nearly every stage of T cell differentiation is the DNA binding protein Tcf-1. Studies proposed here will elucidate how Tcf-1 coordinates the action of epigenetic and transcription regulators to instruct the differentiation of CD4+CD8+ DP thymocytes. Tcf- 1 modulates the chromatin landscapes and transcription profiles directly through binding to its conserved DNA sequence, or indirectly in association with other regulatory proteins. DP thymocytes express two forms of Tcf- 1, the full length Tcf-1p45 protein that binds β-catenin, and a short Tcf-1p38 isoform that does not. Lef-1, another member of the Tcf/Lef family of regulators, also expressed in thymocytes has overlapping functions with Tcf-1. In addition Tcf-1 cooperates with the HLH domain DNA binding protein HEB at the DP thymocyte stages through the sharing of ~7000 DNA binding sites genome wide. The presence of both Tcf-1 and HEB at the shared sites is necessary to promote chromatin accessibility and regulate gene transcription. The direct Tcf-1- HEB binding to their conserved motifs in enhancer regions of T cell differentiation genes promotes their expression. By contrast Tcf-1-HEB recruitment to sites lacking conserved motifs, in promoter regions of cell- cycle genes reduces their expression and cell proliferation. Such opposing transcription outcomes likely involve Tcf-1-HEB recruitment to DNA in the context of distinct regulatory complexes. The composition of complexes containing Tcf-1 and HEB, the specific Tcf-1 isoform involved in each complex, and which functions are redundant between Tcf-1 and Lef-1, still remain to be elucidated. The intricate functional co-operation between these factors likely also involves the ability of Tcf-1 and Lef-1 to bend the DNA helix at their binding site which may modulate the 3D chromatin conformation, and define the proximity between co-operating factors and regulatory elements. These findings and the existing literature provide strong premise for the hypothesis that DP thymocyte development is enabled by the cooperation of Tcf-1 isoforms with protein complexes that shape the 3D chromatin structure to differentially regulate gene expression. Two specific aims are proposed. Aim 1 will determine the how Tcf-1p45 and, Tcf-1p33, co-operate with Lef-1 and HEB in the context of distinct regulatory complexes to establish the epigenetic and transcription profile of DP thymocytes and control their developmental progression. Aim 2: will elucidate the roles of Tcf-1p45, Tcf-1p33, Lef-1 with HEB shaping the chromatin conformation, and how this function promotes DP thymocyte development. The proposed studies are expected to highlight a completely new layer in the molecular regulation of DP thymocytes.

项目总结