E-proteins and EBF1 in B cell differentiation

描述（由申请人提供）：现在已经确定，在普通淋巴样祖细胞（CLPs）中，E2A蛋白可诱导EBF1的表达以建立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E2A，但EBF1位点在转录上保持沉默。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位点被隔离在核层上。然而，在发育成前B细胞后，EBF1基因座从核层迁移到前B细胞的转录许可室。因此，我们现在面临的问题是，EBF1基因座是如何被隔离在核层上的，以及它们在造血祖细胞发育过程中是如何从异染色质中释放出来的。控制这些关键发育调节因子的核位置的因素是理解多能性如何被执行以及B和T谱系如何开始发育的关键。在这里，我们建议研究EBF1基因座在核层的隔离如何与多能性的实施相关。我们将从机制的角度描述EBF1基因座如何从膜层重新定位到常染色质室，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.