Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells

Abstract

The transcription factor PU.1 occupies a central role in controlling myeloid and early B-cell development, and its correct lineage-specific expression is critical for the differentiation choice of hematopoietic progenitors. However, little is known of how this tissue-specific pattern is established. We previously identified an upstream regulatory cis element whose targeted deletion in mice decreases PU.1 expression and causes leukemia. We show here that the upstream regulatory cis element alone is insufficient to confer physiologic PU.1 expression in mice but requires the cooperation with other, previously unidentified elements. Using a combination of transgenic studies, global chromatin assays, and detailed molecular analyses we present evidence that PU.1 is regulated by a novel mechanism involving cross talk between different cis elements together with lineage-restricted autoregulation. In this model, PU.1 regulates its expression in B cells and macrophages by differentially associating with cell type-specific transcription factors at one of its cis-regulatory elements to establish differential activity patterns at other elements. (Blood. 2011;117(10):2827-2838)

The RUNX1–PU.1 axis in the control of hematopoiesis

“…This was later confirmed by genome-wide studies whereby binding of PU.1 revealed factor-specific epigenetic marking of crucial early T-cell differentiation genes [87]. In contrast, low levels of PU.1 expression are specifically required for normal B-cell development, since higher levels drive precursors into myeloid differentiation [88,89]. Similar to T-cells, PU.1 expression is not required for the expression of very early B-cell genes; however, it is essential for the formation of progenitors, as it also regulates the expression of Ebf1 [90].…”

“…Both RUNX1 and PU.1 contain distal regulatory elements harboring RUNX and ETS motifs [16,96], indicating that both genes are subject to autoregulation [44,45,89,97]. Using an inducible system, Lichtinger et al [44] showed that the induction of Runx1 leads to binding of RUNX1 to the proximal promoter and to a strong upregulation of its own expression.…”

“…Intermediate levels of PU.1 expression in B-cells are achieved by a cooperation of PU.1 with E2A and FOXO1 which bind to the -14 Kb URE. In myeloid cells, C/EBP factors activate additional myeloid-specific enhancers at -12 and -10 kb which leads to an upregulation of gene expression through the cooperation of PU.1 and C/EBP factors [89].…”

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

“…However, in other progenitor lineages change in transcription factor activities in the absence of change in expression has been reported. 55 Further study is needed to define the transcriptional events that regulate PGE 2 -induced Flt3 expression in DC progenitor cells.On the basis of these in vitro and in vivo findings, we propose a model in which PGE 2 signaling through the EP1 and EP3 receptors regulates Flt3 expression on DC progenitors. Flt3 receptor signaling activates STAT3 and enhances survivin expression in DC progenitors, which protects them from apoptosis, resulting in optimal DC generation, and that inhibition of PGE 2 signaling impairs DC generation (Figure 6).…”

5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity

“…7,10 Thus the histone code of the PU.1 gene represents an important regulatory mechanism, which remains to be fully understood, to specify different cell fates such as macrophages, granulocytes and lymphocytes. 14 Genetic or epigenetic changes in the PU.1 gene frequently contribute to the pathogenesis of acute myelogenous leukemia (AML). First, deletion of URE in mouse resulted in a decrease of PU.1 to 20% and the onset of AML 12 documenting that PU.1 is a tumor suppressor.…”