E-proteins and EBF1 in B cell differentiation

描述(申请人提供)：现已证实，在常见淋巴系祖细胞(CLP)中，E2a蛋白可诱导EBF1的表达，从而决定B细胞的命运。然而，造血干细胞(HSCs)和多能祖细胞(MPPs)也表达高水平的E2A，但EBF1基因座在转录上保持沉默。这些观察结果提出了一个问题，即为什么EBF1的表达不能被多能祖细胞中的E2A蛋白激活。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，EBF1基因位点隔离在核层。然而，在发育成PRO-B细胞后，EBF1基因座从核板重新定位到PRO-B细胞中转录允许的区域。因此，我们现在面临的问题是，在造血祖细胞的发育过程中，EBF1基因是如何被隔离在核板上的，以及它们从异染色质中释放是如何被调节的。控制这些关键发育调控因子的核心位置的因素是理解多能性是如何实施以及B和T谱系发育是如何启动的关键。在这里，我们建议研究EBF1基因座与核层的隔离如何与多能性的实施有关。我们将用机械术语描述EBF1基因如何从椎板重新定位到常染色质间隔，以协调B细胞的命运。

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.