Blood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation
Open Access
- 24 November 2021
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 219 (1)
- https://doi.org/10.1084/jem.20202490
Abstract
Transcription factors (TFs) regulate cell fates, and their expression must be tightly regulated. Autoregulation is assumed to regulate many TFs’ own expression to control cell fates. Here, we manipulate and quantify the (auto)regulation of PU.1, a TF controlling hematopoietic stem and progenitor cells (HSPCs), and correlate it to their future fates. We generate transgenic mice allowing both inducible activation of PU.1 and noninvasive quantification of endogenous PU.1 protein expression. The quantified HSPC PU.1 dynamics show that PU.1 up-regulation occurs as a consequence of hematopoietic differentiation independently of direct fast autoregulation. In contrast, inflammatory signaling induces fast PU.1 up-regulation, which does not require PU.1 expression or its binding to its own autoregulatory enhancer. However, the increased PU.1 levels induced by inflammatory signaling cannot be sustained via autoregulation after removal of the signaling stimulus. We conclude that PU.1 overexpression induces HSC differentiation before PU.1 up-regulation, only later generating cell types with intrinsically higher PU.1.Funding Information
- Swiss National Science Foundation (179490)
- European Molecular Biology Organization
- Eidgenössische Technische Hochschule Zürich (R01 DK119394)
- SystemsX.ch
This publication has 60 references indexed in Scilit:
- Dissection of a Krox20 positive feedback loop driving cell fate choices in hindbrain patterningMolecular Systems Biology, 2013
- Transcription factors: from enhancer binding to developmental controlNature Reviews Genetics, 2012
- Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cellsBlood, 2011
- Cell-Type-Specific Activation and Repression of PU.1 by a Complex of Discrete, Functionally Specialized cis-Regulatory ElementsMolecular and Cellular Biology, 2010
- A Recurrent Network Involving the Transcription Factors PU.1 and Gfi1 Orchestrates Innate and Adaptive Immune Cell FatesImmunity, 2009
- The Pu.1 Locus Is Differentially Regulated at the Level of Chromatin Structure and Noncoding Transcription by Alternate Mechanisms at Distinct Developmental Stages of HematopoiesisMolecular and Cellular Biology, 2007
- Elucidation of the Phenotypic, Functional, and Molecular Topography of a Myeloerythroid Progenitor Cell HierarchyCell Stem Cell, 2007
- Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptorsBlood, 2006
- Regulatory Dynamics of Synthetic Gene Networks with Positive FeedbackJournal of Molecular Biology, 2006
- Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1Nature Genetics, 2004