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）：现已明确，在普通淋巴祖细胞（CLP）中，E2 A蛋白可诱导EBF 1表达，从而确定B细胞命运。然而，造血干细胞（HSC）和多能祖细胞（MPP）也表达高水平的E2 A，但EBF 1基因座保持转录沉默。这些观察结果提出了一个问题，为什么E2 A蛋白在多能祖细胞中不激活EBF 1表达。最近的高通量染色体构象捕获（Hi-C）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，EBF 1基因座被隔离在核板层。然而，在发育成原B细胞后，EBF 1基因座从核纤层重新定位到原B细胞中的转录允许区室。因此，我们现在面临的问题是，EBF 1基因座是如何被隔离在核纤层，以及如何从异染色质中释放的造血祖细胞的发展过程中进行调节。控制这些关键发育调节因子的核定位的因素是理解多能性是如何实施的以及B和T谱系发育是如何启动的关键。在这里，我们建议研究如何螯合的EBF 1基因座的核板涉及到执行的多能性。我们将描述在机制方面如何EBF 1基因座从板搬迁到常染色质区室，以协调B细胞的命运。