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PMID: 15947094 Published · ppublish English Journal Article

Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages.

Blood ·Vol. 106 ·No. 6 ·2005-09-15 ·Pages 1938-47

Tamura T, Thotakura P, Tanaka TS, Ko MS, Ozato K

Abstract

Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence-binding protein (ICSBP) is a transcription factor that controls myeloid-cell development. Microarray gene expression analysis of Irf-8-/- myeloid progenitor cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8-induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation.

MeSH Terms
Animals Base Sequence Binding Sites Cathepsin C/genetics Cell Differentiation/genetics Cell Line Chromatin Immunoprecipitation Consensus Sequence Cystatin C Cystatins/genetics Enhancer Elements, Genetic/genetics Gene Expression Regulation Genes, Reporter Interferon Regulatory Factors Macrophages/cytology,metabolism Mice Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Repressor Proteins/physiology Transcription, Genetic
Chemicals
Cst3 protein, mouse Cystatin C Cystatins Interferon Regulatory Factors Repressor Proteins interferon regulatory factor-8 Cathepsin C
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tamura Tomohiko
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, 6 Center Dr, MSC 2753, Bethesda, MD 20892-2753, USA. [email protected]
Thotakura Pratima
Tanaka Tetsuya S
Ko Minoru S H
Ozato Keiko
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-01-0080
Email
[email protected]
Published
2005-09-15
Epub
2005-00-09
Pages
1938-47
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895144
Subset
IM
External Links
PubMed source DOI: 10.1182/blood-2005-01-0080 PMC Full Text View journal details
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