title: Dynamic analysis of gene expression and genome-wide transcription factor binding during lineage specification of multipotent progenitors.
abstract: We used the paradigmatic GATA-PU.1 axis to explore, at the systems level, dynamic relationships between transcription factor (TF) binding and global gene expression programs as multipotent cells differentiate. We combined global ChIP-seq of GATA1, GATA2, and PU.1 with expression profiling during differentiation to erythroid and neutrophil lineages. Our analysis reveals (1) differential complexity of sequence motifs bound by GATA1, GATA2, and PU.1; (2) the scope and interplay of GATA1 and GATA2 programs within, and during transitions between, different cell compartments, and the extent of their hard-wiring by DNA motifs; (3) the potential to predict gene expression trajectories based on global associations between TF-binding data and target gene expression; and (4) how dynamic modeling of DNA-binding and gene expression data can be used to infer regulatory logic of TF circuitry. This rubric exemplifies the utility of this cross-platform resource for deconvoluting the complexity of transcriptional programs controlling stem/progenitor cell fate in hematopoiesis.
authors.affiliation: Stem Cell Group, UCL Cancer Institute, University College London, London WC1E 6BT, UK; Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: May
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Tipping
authors.forename: Jose
authors.initials: J
authors.lastname: Teles
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.forename: Mengchu
authors.initials: M
authors.lastname: Wu
authors.forename: Yanping
authors.initials: Y
authors.lastname: Guo
authors.forename: Cristina
authors.initials: C
authors.lastname: Fugazza
authors.forename: John
authors.initials: J
authors.lastname: Brown
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Cristina
authors.initials: C
authors.lastname: Pina
authors.forename: Victor
authors.initials: V
authors.lastname: Olariu
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Carsten
authors.initials: C
authors.lastname: Peterson
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
mesh_terms: D000818:Animals; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D059372:Nucleotide Motifs / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1