Key regulators control distinct transcriptional programmes in blood progenitor and mast cells.
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.
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK fjc28@cam.ac.uk bg200@cam.ac.uk.
Fernando J
FJ
Calero-Nieto
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Felicia S
FS
Ng
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Nicola K
NK
Wilson
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Rebecca
R
Hannah
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Victoria
V
Moignard
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Ana I
AI
Leal-Cervantes
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Isabel
I
Jimenez-Madrid
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK.
Evangelia
E
Diamanti
MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK.
Lorenz
L
Wernisch
Department of Haematology, Wellcome Trust and MRC Cambridge Stem Cell Institute, Cambridge Institute for Medical Research, Cambridge University, Cambridge, UK fjc28@cam.ac.uk bg200@cam.ac.uk.
Berthold
B
Göttgens
D000818:Animals; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D017930:Genes, Reporter; D055106:Genome-Wide Association Study; D006410:Hematopoiesis / Q000235:genetics; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D015233:Models, Statistical; D059372:Nucleotide Motifs; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
D014157:Transcription Factors
gene regulation; haematopoiesis; mast cells; progenitors