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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901411v1 183/6/3839    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Good, S. R. Articles by Kaplan, M. H. PubMed PubMed Citation Articles by Good, S. R. Articles by Kaplan, M. H.

Temporal Induction Pattern of STAT4 Target Genes Defines Potential for Th1 Lineage-Specific Programming¹

Seth R. Good^2,*, Vivian T. Thieu^2,, Anubhav N. Mathur, Qing Yu, Gretta L. Stritesky, Norman Yeh, John T. O'Malley, Narayanan B. Perumal^3,* and Mark H. Kaplan^3,

^* School of Informatics, Indiana University-Purdue University Indianapolis; and Departments of Pediatrics, H.B. Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202

STAT4 is a critical component in the development of inflammatory adaptive immune responses. It has been extensively characterized as a lineage-determining factor in Th1 development. However, the genetic program activated by STAT4 that results in an inflammatory cell type is not well defined. In this report, we use DNA isolated from STAT4-chromatin immunoprecipitation to perform chromatin immunoprecipitation-on-chip analysis of over 28,000 mouse gene promoters to identify STAT4 targets. We demonstrate that STAT4 binds multiple gene-sets that program distinct components of the Th1 lineage. Although many STAT4 target genes display STAT4-dependent IL-12-inducible expression, other genes displayed IL-12-induced histone modifications but lack induction, possibly due to high relative basal expression. In the subset of genes that STAT4 programs for expression in Th1 cells, IL-12-induced mRNA levels remain increased for a longer time than mRNA from genes that are not programmed. This suggests that STAT4 binding to target genes, while critical, is not the only determinant for STAT4-dependent gene programming during Th1 differentiation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grant AI45515 (to M.H.K.). G.L.S., N.Y., and J.T.O. were supported by T32AI060519; V.T.T. was supported by T32HL007910.

² S.R.G. and V.T.T. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Mark H. Kaplan, Departments of Pediatrics, and Microbiology, and Immunology, Indiana University School of Medicine, H.B. Wells Center for Pediatric Research, 702 Barnhill Drive, RI 2600, Indianapolis, IN 46202 or Dr. Narayanan B. Perumal, School of Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202. E-mail address: mkaplan2{at}iupui.edu or nperumal{at}iupui.edu

⁴ Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; qPCR, quantitative (real-time) PCR; GO, gene ontology; TSS, transcription start site; MEME, multiple expectation maximization for motif elicitation.

⁵ The online version of this article contains supplemental material.

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The JI 2009 183: 3557-3558. [Full Text]