E-proteins and EBF1 in B cell differentiation

B 细胞分化中的 E 蛋白和 EBF1

• 批准号: 8697726
• 负责人: CORNELIS MURRE
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8697726
• 关键词: Adult; Alleles; Antibody Formation; B cell differentiation; B-Cell Development; B-Lymphocytes; Binding Sites; Bone Marrow; Cell Lineage; Cells; Chromatin; Chromosomes; Commit; Common Lymphoid Progenitor; DNA Methylation; Development; Dissociation; E protein; Embryo; Environment; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Goals; Hematopoietic; Hematopoietic stem cells; Heterochromatin; Human; Immunoglobulin-Secreting Cells; Leukocytes; Location; Mediating; Methods; Molecular; Molecular Conformation; Multipotent Stem Cells; Mus; Names; Nuclear; Nuclear Lamina; Nucleic Acid Regulatory Sequences; Positioning Attribute; Proteins; Regulatory Element; Role; Specialist; Staging; Stem cells; Structure; Sum; T-Lymphocyte; TCF3 gene; Time; base; embryonic stem cell; insight; mutant; premature; progenitor; programs; public health relevance; stem; transcription factor

DESCRIPTION (provided by applicant): It is now well established that in common lymphoid progenitors (CLPs), the E2A proteins act to induce the expression of EBF1 to establish B cell fate. However, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) also express high levels of E2A, yet the EBF1 locus remains transcriptionally silent. These observations have raised the question as to why EBF1 expression is not activated by the E2A proteins in multipotent progenitors. Recent High-Throughput Chromosome Conformation Capture (Hi-C) studies have provided unexpected insights into this question. These studies showed that in multipotent progenitor cells the EBF1 locus is sequestered at the nuclear lamina. However, upon developing into pro- B cells the EBF1 locus relocates from the nuclear lamina to the transcriptionally permissive compartment in pro-B cells. Thus, we are now faced with the question as to how the EBF1 locus is sequestered at the nuclear lamina and how their release from the heterochromatin is regulated during the progression of developing hematopoietic progenitors. Factors that control the nuclear location of these key developmental regulators are the key to understanding how multipotency is enforced and how B and T lineage development is initiated. Here we propose to examine how sequestration of the EBF1 locus to the nuclear lamina relates to the enforcement of multipotency. We would describe in mechanistic terms how the EBF1 locus relocates from the lamina to the euchromatic compartment to orchestrate B cell fate.

描述（由申请人提供）：现在已经很好地确定，在常见的淋巴祖细胞（CLP）中，E2A蛋白起作用可诱导EBF1的表达以建立B细胞命运。但是，造血干细胞（HSC）和多能（MPP）也表达高水平的E2A，但EBF1基因座仍保持转录静音。这些观察结果提出了一个问题，即为什么在多能祖细胞中E2A蛋白不激活EBF1表达。最近的高通量染色体构象捕获（HI-C）的研究为这个问题提供了意想不到的见解。这些研究表明，在多能祖细胞中，EBF1基因座在核层片上被隔离。然而，在发展成pro细胞后，EBF1基因座从核薄片重新定位到pro-B细胞中的转录允许区室。因此，我们现在面临着一个问题，即在核层中如何隔离EBF1基因座，以及它们如何从异染色质中释放在发生造血祖细胞的过程中。控制这些关键发展调节剂的核位置的因素是了解如何实施多重企业以及如何启动B和T谱系发展的关键。在这里，我们建议研究EBF1基因座对核层次的隔离如何与多重执行有关。我们将用机械术语来描述EBF1基因座如何从薄片中重新定位到正式室，以编排B细胞命运。