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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.

TitleGfi1 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.
Publication TypeJournal Article
Year of Publication2010
AuthorsWilson NK, Timms RT, Kinston SJ, Cheng Y-H, S Oram H, Landry J-R, Mullender J, Ottersbach K, Göttgens B
JournalMol Cell Biol
Volume30
Issue15
Pagination3853-63
Date Published2010 Aug
ISSN1098-5549
KeywordsAnimals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Chromatin Immunoprecipitation, Hematopoiesis, Hematopoietic Stem Cells, Hematopoietic System, Homeodomain Proteins, Intercellular Signaling Peptides and Proteins, Mice, Mice, Transgenic, Neoplasm Proteins, Proto-Oncogene Proteins, Regulatory Sequences, Nucleic Acid
Abstract

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.

DOI10.1128/MCB.00032-10
Alternate JournalMol. Cell. Biol.
PubMed ID20516218
PubMed Central IDPMC2916401
Grant ListG0800784 / / Medical Research Council / United Kingdom
/ / Cancer Research UK / United Kingdom
/ / Medical Research Council / United Kingdom
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