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Lmo2-Lyl1 and the bHLH factor network in pro-T cells

pro-T 细胞中的 Lmo2-Lyl1 和 bHLH 因子网络

基本信息

批准号：
10427443
负责人：
ELLEN V. ROTHENBERG
金额：
$ 61.34万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10427443
关键词：
Acute Acute Lymphocytic Leukemia Affect B-Lymphocytes BHLH Protein Benign Binding Biochemical Cell Cycle Cell Differentiation process Cell Lineage Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Development Dose Down-Regulation E protein Enzymes Event GATA3 gene Gene Expression Gene Rearrangement Genes Genome Genomics Helix-Turn-Helix Motifs Heterodimerization Human Immune Immune system In Vitro Inhibitor of Differentiation Proteins Kinetics Lymphoid Cell Molecular Monitor Mutate Normal Cell Oncogenes Phase Phenotype Population Dynamics Process Proliferating Property Proto-Oncogenes Rag1 Mouse Regulation Regulator Genes Regulatory Element Role Site T cell differentiation T-Cell Development T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte TCF3 gene Testing Thymus Gland Tumor stage Work base dimer gene network gene product gene regulatory network genetic signature genome-wide in vivo leukemia network architecture preservation prevent programs protein complex response stem cells transcription factor

项目摘要

PROJECT SUMMARY The progression of T cell precursors from multipotency to commitment occurs after multiple cell cycles in the thymus. These early, pre-commitment cell cycles are important for expansion of the precursors to generate enough pro-T cells to survive later selection events. However, the early stages are poorly understood, and in particular it has not been clear what controls the precise trajectory of the cells' differentiation nor the timing or irreversibility of commitment when it occurs. Genomic regulatory elements that are active after commitment tend to be characterized by motifs for basic helix-loop-helix (bHLH) E proteins, E2A or HEB, whereas those that are active before commitment have other signatures, suggesting that there is a major increase in E protein activity across this transition. In fact, the expression of E proteins is almost equally high before commitment, but our recent data show that they are occupied in substantially different roles before commitment, in complexes with other heterodimerization partners. This proposal is based on recent evidence that the alternative complex, containing Lmo2 and Lyl1 dimerized with E2A or HEB, may actually be a major controller of the commitment transition in early T cells. Our recent evidence shows that expression of Lmo2 and Lyl1 is sufficient to make committed pro-T cells reverse their differentiation in terms of gene expression. Not only does the Lmo2/Lyl1/E2A complex bind to different genomic sites than E protein dimers, but also the addition of Lmo2 and Lyl1 to committed pro-T cells is sufficient to remove E proteins from sites that they occupy after commitment and shift them to sites that are normally active only before commitment. The implication is that the kinetics of downregulation of Lmo2 and Lyl1 in normal T-cell differentiation could be vital for determining the timing of commitment and of the maturation of the pro-T cells. Lmo2 and Lyl1 have been considered as T- lineage proto-oncogenes, but our evidence suggests a potent role in normal development. This proposal is to determine the mechanism of how this works and to test its significance for the actual developmental dynamics of normal early T cells. Our preliminary work identifies the signature target genes affected by Lmo2+Lyl1 and their overlap with genes expressed in normal pro-T cells. We now propose to define: (1) the distinct molecular mechanisms that control different subsets of these signature genes, based on genome-wide mapping of the chromatin state changes caused by Lmo2+Lyl1/E protein complex binding as compared to pure E protein dimer binding; (2) whether endogenous Lmo2/Lyl1/E protein complexes indeed control differentiation kinetics and commitment of normal pro-T cells, based on acute CRISPR and monitoring in vitro and in vivo; and (3) the gene regulatory network architecture, involving factors regulated by Lmo2+Lyl1, through which Lmo2+Lyl1 exert their surprisingly broad impacts on T cell development. The results should determine whether and how a biochemical mechanism of transcription factor heterodimerization partner switching may explain a central unsolved problem in the dynamics of T cell development.

项目总结