Abstract
All mature blood cells derive from hematopoietic stem cells through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs) and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most-studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications, and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e., prevent or promote) the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when, and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and TFs.
Highlights
The character of a cell type is defined by its specific transcriptional program, which is regulated by transcription factors (TFs) that bind DNA cis-regulatory elements to activate or repress defined set of genes
Prominent among those are E2A, Early B cell factor 1 (Ebf1), and Pax5, as well as other TFs acting downstream and upstream to these www.frontiersin.org factors. Some of these TFs such as Ebf1 and Pax5 are restricted to the B cell lineage while others such as Ikaros, PU.1, E2A, and FoxO1 are involved in other lineage fate determination. The expression of these TFs is temporally regulated; e.g., Ikaros, PU.1, and E2A are expressed in the very early progenitors including hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) before the commitment to the lymphoid branch, Ebf1 and FoxO1 are expressed at the common lymphoid progenitors (CLPs) stage under the control of E2A [24] and Pax5 expression is induced by the concerted action of Ebf1, FoxO1, and E2A in committed pro-B cells
Motif analysis of cell type-specific PU.1 binding sites revealed that PU.1 binds in vicinity of lineagespecific TFs: B cell-specific PU.1 binding sites are enriched in E2A, Ebf1, OCT, and NF-kB motifs, while macrophage-specific sites are enriched in C/EBP and AP-1 motifs [30]. These findings strongly suggest that the cell type-specific function of PU.1 is partly due to its collaborative interaction with other lineage-specific TFs
Summary
The character of a cell type is defined by its specific transcriptional program, which is regulated by transcription factors (TFs) that bind DNA cis-regulatory elements (cis-REs) to activate or repress defined set of genes. The expression of these TFs is temporally regulated; e.g., Ikaros, PU.1, and E2A are expressed in the very early progenitors including HSCs and MPPs before the commitment to the lymphoid branch, Ebf1 and FoxO1 are expressed at the CLP stage under the control of E2A [24] and Pax5 expression is induced by the concerted action of Ebf1, FoxO1, and E2A in committed pro-B cells.
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