Gfi1 Expression Is Controlled by Five Distinct Regulatory Regions Spread over 100 Kilobases, with Scl/Tal1, Gata2, PU.1, Erg, Meis1, and Runx1 Acting as Upstream Regulators in Early Hematopoietic Cells
| Autor: | Richard T. Timms, Katrin Ottersbach, Nicola K. Wilson, Yi-Han Cheng, Berthold Göttgens, Josette-Renee Landry, Joanne Mullender, S. Helen Oram, Sarah Kinston |
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| Rok vydání: | 2010 |
| Předmět: |
Chromatin Immunoprecipitation
Hematopoietic System Cellular differentiation Mice Transgenic Regulatory Sequences Nucleic Acid Biology Cell Line Mice Proto-Oncogene Proteins Basic Helix-Loop-Helix Transcription Factors medicine Animals Myeloid Ecotropic Viral Integration Site 1 Protein Enhancer Molecular Biology Transcription factor T-Cell Acute Lymphocytic Leukemia Protein 1 Homeodomain Proteins Genetics GATA2 Hematopoietic stem cell Cell Differentiation Articles Cell Biology Hematopoietic Stem Cells Hematopoiesis Neoplasm Proteins Cell biology medicine.anatomical_structure Regulatory sequence Intercellular Signaling Peptides and Proteins Stem cell Chromatin immunoprecipitation |
| Zdroj: | Molecular and Cellular Biology. 30:3853-3863 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00032-10 |
| Popis: | The growth factor independence 1 (Gfi1) gene was originally discovered in the hematopoietic system, where it functions as a key regulator of stem cell homeostasis, as well as neutrophil and T-cell development. Outside the blood system, Gfi1 is essential for inner-ear hair and intestinal secretory cell differentiation. To understand the regulatory hierarchies within which Gfi1 operates to control these diverse biological functions, we used a combination of comparative genomics, locus-wide chromatin immunoprecipitation assays, functional validation in cell lines, and extensive transgenic mouse assays to identify and characterize the complete ensemble of Gfi1 regulatory elements. This concerted effort identified five distinct regulatory elements spread over 100kb each driving expression in transgenic mice to a subdomain of endogenous Gfi1. Detailed characterization of an enhancer 35 kb upstream of Gfi1 demonstrated activity in the dorsal aorta region and fetal liver in transgenic mice, which was bound by key stem cell transcription factors Scl/Tal1, PU.1/Sfpi1, Runx1, Erg, Meis1, and Gata2. Taken together, our results reveal the regulatory regions responsible for Gfi1 expression and importantly establish that Gfi1 expression at the sites of hematopoietic stem cell (HSC) emergence is controlled by key HSC regulators, thus integrating Gfi1 into the wider HSC regulatory networks. |
| Databáze: | OpenAIRE |
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