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

Ellen V Rothenberg,Jonas Ungerbäck,Hiroyuki Hosokawa

doi:10.3389/fimmu.2019.00228

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.

Highlights

PU.1 Expression in Precursors of T CellsPU.1, encoded by the Spi1 gene, is an ETS-family transcription factor with multiple roles in hematopoiesis
The developmental scope of PU.1 activity is surprisingly broad, and one of its unexpected domains of action is in the early stages of T-cell development, in both the fetal and the postnatal mammalian thymus. To examine what it does in pro-T cells, this review focuses on recent data based on mouse T-cell development, mostly as it occurs in the postnatal thymus or from late fetal progenitors
The genomic sites that were most highly associated with these responses in primary proT cells were developmentally dynamic in chromatin accessibility: normally open in early stages of T-cell development but closed once the cells went through commitment

Summary

INTRODUCTION

PU., encoded by the Spi gene, is an ETS-family transcription factor with multiple roles in hematopoiesis. The genomic sites that were most highly associated with these responses in primary proT cells were developmentally dynamic in chromatin accessibility: normally open in early stages of T-cell development (endogenous PU.1-expressing) but closed once the cells went through commitment (endogenous PU.1-low or negative). The impact of PU. on pro-T cell gene expression overall is at odds with the biochemical and genomic evidence for its mode of action in one respect: PU. introduced into primary proT cells or Scid.adh.2C2 cells causes downregulation of many T-cell genes, especially those associated with Notch signaling and TCR gene rearrangement after commitment This response is fast, reducing existing transcript pools for many repressed genes even before most positively regulated PU. target genes are seen to be turned on [80].

GO biological process complete

Regulation of multicellular organismal

CONCLUSIONS AND FUTURE QUESTIONS