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Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1

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Item Type:Article
Title:Mechanisms of in vivo binding site selection of the hematopoietic master transcription factor PU.1
Creators Name:Pham, T.H. and Minderjahn, J. and Schmidl, C. and Hoffmeister, H. and Schmidhofer, S. and Chen, W. and Laengst, G. and Benner, C. and Rehli, M.
Abstract:The transcription factor PU.1 is crucial for the development of many hematopoietic lineages and its binding patterns significantly change during differentiation processes. However, the 'rules' for binding or not-binding of potential binding sites are only partially understood. To unveil basic characteristics of PU.1 binding site selection in different cell types, we studied the binding properties of PU.1 during human macrophage differentiation. Using in vivo and in vitro binding assays, as well as computational prediction, we show that PU.1 selects its binding sites primarily based on sequence affinity, which results in the frequent autonomous binding of high affinity sites in DNase I inaccessible regions (25-45% of all occupied sites). Increasing PU.1 concentrations and the availability of cooperative transcription factor interactions during lineage differentiation both decrease affinity thresholds for in vivo binding and fine-tune cell type-specific PU.1 binding, which seems to be largely independent of DNA methylation. Occupied sites were predominantly detected in active chromatin domains, which are characterized by higher densities of PU.1 recognition sites and neighboring motifs for cooperative transcription factors. Our study supports a model of PU.1 binding control that involves motif-binding affinity, PU.1 concentration, cooperativeness with neighboring transcription factor sites and chromatin domain accessibility, which likely applies to all PU.1 expressing cells.
Keywords:Base Sequence, Binding Sites, Chromatin, Consensus Sequence, Deoxyribonuclease I, DNA, Macrophages, Monocytes, Nucleotide Motifs, Protein Binding, Proto-Oncogene Proteins, Stem Cells, Trans-Activators
Source:Nucleic Acids Research
ISSN:0305-1048
Publisher:Oxford University Press (U.K.)
Volume:41
Number:13
Page Range:6391-6402
Date:July 2013
Official Publication:https://doi.org/10.1093/nar/gkt355
PubMed:View item in PubMed

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