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.
The production of antibodies is generated in specialist white blood cells. Specifically these cells are named B cells. They originate in the bone marrow of adult mice and humans. During the past two decades key molecules have been identified that orchestrate the development of antibody secreting cells from the stem cells in the bone marrow. However, it still is unclear as to how the Big Bang of B cell development is initiated. Here we propose studies that aim to reveal these very early stages of B cell development.
|Bossen, Claudia; Murre, Caroline S; Chang, Aaron N et al. (2015) The chromatin remodeler Brg1 activates enhancer repertoires to establish B cell identity and modulate cell growth. Nat Immunol 16:775-84|
|Chandra, Vivek; Bortnick, Alexandra; Murre, Cornelis (2015) AID targeting: old mysteries and new challenges. Trends Immunol 36:527-35|