Journal
EMBO JOURNAL
Volume 33, Issue 11, Pages 1212-1226Publisher
WILEY
DOI: 10.1002/embj.201386825
Keywords
gene regulation; haematopoiesis; mast cells; progenitors
Categories
Funding
- Leukaemia and Lymphoma Research
- Medical Research Council
- Leukaemia and Lymphoma Society
- Cancer Research UK
- National Institute for Health Research Cambridge Biomedical Research Centre
- Wellcome Trust
- Yousef Jameel scholarship
- MRC Cambridge Stem Cell Institute
- BBSRC [BB/I00050X/1] Funding Source: UKRI
- MRC [G0900951, MC_U105260799] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/I00050X/1, BBS/B/1454X] Funding Source: researchfish
- Cancer Research UK [12765] Funding Source: researchfish
- Medical Research Council [MC_PC_12009, MC_U105260799, G0900951] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900729/1] Funding Source: researchfish
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Despite major advances in the generation of genome-wide binding maps, the mechanisms by which transcription factors (TFs) regulate cell type identity have remained largely obscure. Through comparative analysis of 10 key haematopoietic TFs in both mast cells and blood progenitors, we demonstrate that the largely cell type-specific binding profiles are not opportunistic, but instead contribute to cell type-specific transcriptional control, because (i) mathematical modelling of differential binding of shared TFs can explain differential gene expression, (ii) consensus binding sites are important for cell type-specific binding and (iii) knock-down of blood stem cell regulators in mast cells reveals mast cell-specific genes as direct targets. Finally, we show that the known mast cell regulators Mitf and c-fos likely contribute to the global reorganisation of TF binding profiles. Taken together therefore, our study elucidates how key regulatory TFs contribute to transcriptional programmes in several distinct mammalian cell types.
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