title: Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators.
abstract: Hematopoietic differentiation critically depends on combinations of transcriptional regulators controlling the development of individual lineages. Here, we report the genome-wide binding sites for the five key hematopoietic transcription factors--GATA1, GATA2, RUNX1, FLI1, and TAL1/SCL--in primary human megakaryocytes. Statistical analysis of the 17,263 regions bound by at least one factor demonstrated that simultaneous binding by all five factors was the most enriched pattern and often occurred near known hematopoietic regulators. Eight genes not previously appreciated to function in hematopoiesis that were bound by all five factors were shown to be essential for thrombocyte and/or erythroid development in zebrafish. Moreover, one of these genes encoding the PDZK1IP1 protein shared transcriptional enhancer elements with the blood stem cell regulator TAL1/SCL. Multifactor ChIP-Seq analysis in primary human cells coupled with a high-throughput in vivo perturbation screen therefore offers a powerful strategy to identify essential regulators of complex mammalian differentiation processes.
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Marloes R
authors.initials: MR
authors.lastname: Tijssen
authors.forename: Ana
authors.initials: A
authors.lastname: Cvejic
authors.forename: Anagha
authors.initials: A
authors.lastname: Joshi
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Hannah
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.forename: Ariel
authors.initials: A
authors.lastname: Forrai
authors.forename: Dana C
authors.initials: DC
authors.lastname: Bellissimo
authors.forename: S Helen
authors.initials: SH
authors.lastname: Oram
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smethurst
authors.forename: Nicola K
authors.initials: NK
authors.lastname: Wilson
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Wang
authors.forename: Katrin
authors.initials: K
authors.lastname: Ottersbach
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Green
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D002454:Cell Differentiation; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000378:metabolism*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; D051789:Proto-Oncogene Protein c-fli-1; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C078433:FLI1 protein, human; C494688:GATA1 protein, human; C494711:GATA2 protein, human; C493728:RUNX1 protein, human; C067143:TAL1 protein, human