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Chromatin Remodeler Recruitment during Macrophage Differentiation Facilitates Transcription Factor Binding to Enhancers in Mature Cells.

Authors
  • McAndrew, Michael J1, 2
  • Gjidoda, Alison2
  • Tagore, Mohita1, 2
  • Miksanek, Tyler2
  • Floer, Monique3, 2
  • 1 the Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824.
  • 2 From the Department of Biochemistry and Molecular Biology and.
  • 3 the Genetics Graduate Program, Michigan State University, East Lansing, Michigan 48824 [email protected]
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Aug 26, 2016
Volume
291
Issue
35
Pages
18058–18071
Identifiers
DOI: 10.1074/jbc.M116.734186
PMID: 27382057
Source
Medline
Keywords
License
Unknown

Abstract

We show how enhancers of macrophage-specific genes are rendered accessible in differentiating macrophages to allow their induction in mature cells in response to an appropriate stimulus. Using a lentiviral knockdown approach in primary differentiating macrophages from mouse bone marrow, we demonstrate that enhancers of Il12b and Il1a are kept relatively lowly occupied by nucleosomes and accessible through recruitment of the nucleosome remodeler BAF/PBAF. Our results using an inducible cell line that expresses an estrogen receptor fusion of the macrophage-specific transcription factor PU.1 (PUER) show that BAF/PBAF recruitment to these enhancers is a consequence of translocation of PUER to the nucleus in the presence of tamoxifen, and we speculate that remodeler recruitment may be directly mediated by PU.1. In the absence of BAF/PBAF recruitment, nucleosome occupancy at the enhancer of Il12b (and to a lesser extent at Il1a) reaches high levels in bone marrow-derived macrophages (BMDMs), and the enhancers are not fully cleared of nucleosomes upon LPS induction, resulting in impaired gene expression. Analysis of Il12b expression in single cells suggests that recruitment of the remodeler is necessary for high levels of transcription from the same promoter, and we propose that remodelers function by increasing nucleosome turnover to facilitate transcription factor over nucleosome binding in a process we have termed "remodeler-assisted competition."

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