Genome-wide Analysis of Simultaneous GATA1/2, RUNX1, FLI1, and SCL Binding in Megakaryocytes Identifies Hematopoietic Regulators

• DOI: 10.1016/j.devcel.2011.04.008
• Publication Date: 2011-05-22T14:36:12Z
• Authors: Marloes R. Tijssen; Ana Cvejic; Anagha Joshi; Rebecca L. Hannah; Rita Ferreira; Ariel Forrai; Dana C. Bellissimo; S. Helen Oram; Peter A. Smethurst; Nicola K. Wilson; Xiaonan Wang; Katrin Ottersbach; Derek L. Stemple; Anthony R. Green; Willem H. Ouwehand; Berthold Göttgens
• Keywords: 0303 health sciences; Binding Sites; Genome, Human; Proto-Oncogene Protein c-fli-1; Cell Differentiation; Article; GATA2 Transcription Factor; 03 medical and health sciences; Proto-Oncogene Proteins; Core Binding Factor Alpha 2 Subunit; Basic Helix-Loop-Helix Transcription Factors; Humans; GATA1 Transcription Factor; /dk/atira/pure/subjectarea/asjc/1300/1309; Megakaryocytes; Cells, Cultured; T-Cell Acute Lymphocytic Leukemia Protein 1; Developmental Biology; Oligonucleotide Array Sequence Analysis

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.