C/EBPα Activates Pre-existing and De Novo Macrophage Enhancers during Induced Pre-B Cell Transdifferentiation and Myelopoiesis

Research output: Contribution to journalArticle

Authors

  • Chris van Oevelen
  • Samuel Collombet
  • Guillermo Vicent
  • Cyrille Lepoivre
  • Aimee Badeaux
  • Lars Bussmann
  • Jose Luis Sardina
  • Denis Thieffry
  • Miguel Beato
  • Yang Shi
  • Thomas Graf

Colleges, School and Institutes

Abstract

Transcription-factor-induced somatic cell conversions are highly relevant for both basic and clinical research yet their mechanism is not fully understood and it is unclear whether they reflect normal differentiation processes. Here we show that during pre-B-cell-to-macrophage transdifferentiation, C/EBPα binds to two types of myeloid enhancers in B cells: pre-existing enhancers that are bound by PU.1, providing a platform for incoming C/EBPα; and de novo enhancers that are targeted by C/EBPα, acting as a pioneer factor for subsequent binding by PU.1. The order of factor binding dictates the upregulation kinetics of nearby genes. Pre-existing enhancers are broadly active throughout the hematopoietic lineage tree, including B cells. In contrast, de novo enhancers are silent in most cell types except in myeloid cells where they become activated by C/EBP factors. Our data suggest that C/EBPα recapitulates physiological developmental processes by short-circuiting two macrophage enhancer pathways in pre-B cells.

Details

Original languageEnglish
Pages (from-to)232-247
JournalStem Cell Reports
Volume5
Issue number2
Early online date30 Jul 2015
Publication statusPublished - 11 Aug 2015