Mechanisms of Action of Hematopoietic Transcription Factor PU.1 in Initiation of T-Cell Development

Abstract

PU.1 is an ETS-family transcription factor that plays a broad range of roles in hematopoiesis. A direct regulator of myeloid, dendritic-cell, and B cell functional programs, and a well-known antagonist of terminal erythroid cell differentiation, it is also expressed in the earliest stages of T-cell development of each cohort of intrathymic pro-T cells. Its expression in this context appears to give T-cell precursors initial, transient access to myeloid and dendritic cell developmental competence and therefore to represent a source of antagonism or delay of T-cell lineage commitment. However, it has remained uncertain until recently why T-cell development is also intensely dependent upon PU.1. Here, we review recent work that sheds light on the molecular biology of PU.1 action across the genome in pro-T cells and identifies the genes that depend on PU.1 for their correct regulation. This work indicates modes of chromatin engagement, pioneering, and cofactor recruitment (“coregulator theft”) by PU.1 as well as gene network interactions that not only affect specific target genes but also have system-wide regulatory consequences, amplifying the impact of PU.1 beyond its own direct binding targets. The genes directly regulated by PU.1 also suggest a far-reaching transformation of cell biology and signaling potential between the early stages of T-cell development when PU.1 is expressed and when it is silenced. These cell-biological functions can be important to distinguish fetal from adult T-cell development and have the potential to illuminate aspects of thymic function that have so far remained the most mysterious.

Programming for T-lymphocyte fates: modularity and mechanisms

“…Remarkably, however, overexpression of the essential T-cell transcription factor GATA3 itself in precommitment T-lineage precursors can direct them to become mast cells instead within a few days (Taghon et al 2007). Also, while postcommitment T-cell precursors and mature T cells are functionally very distinct from macrophages and neutrophils, precommitment T-cell precursors (ETP and DN2a) also naturally express substantial levels of the myeloid transcription factor PU.1, which is not only sustained through multiple cell divisions but also plays a necessary positive role in their early development (Dakic et al 2005;Champhekar et al 2015; for review, see Rothenberg et al 2019). PU.1 expression is turned off during lineage commitment, as discussed below, but, before this, PU.1expressing T-cell precursors can efficiently differentiate into granulocytes, macrophages, and dendritic cells instead of T cells if they are removed from the Notch ligands of the thymus and placed in a myeloid-supportive environment (Balciunaite et al 2005;Bell and Bhandoola 2008;Wada et al 2008;Yui et al 2010;Kueh et al 2016).…”

Transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis

“…during lymphocyte B cell development and is involved in disease like Inflammatory diarrhea, primary mediastinal B cell Lymphoma and pediatric T cell acute lymphoblastic leukemia. 44,45 FPR2 works as a chemoattractant receptor involved in antibacterial host defense and inflammation through sensing of bacteria 46 which is expressed not only by immune cells, but also epithelial, endothelial and fibroblasts cells 47 that elicits proinflammatory responses. FPR2 also promotes monocytes inflammatory activities and its absence in knock-out mice results in increased bacteria load in the liver and reduced neutrophil infiltration.…”

A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

“…3e). PU.1 (Spi.1), which is normally undetectable in mature T cells, was also expressed, and the genes up-regulated by PU.1 such as Bcl11a, Lmo2, Mef2c, Syk, Lyn and Cd300a, but not Bcl11b, were up-regulated (54,56,57) (Fig. 3e).…”