Dynamic BRG1 Recruitment during T Helper Differentiation and Activation Reveals Distal Regulatory Elements

Abstract

T helper cell differentiation and activation require specific transcriptional programs accompanied by changes in chromatin structure. However, little is known about the chromatin remodeling enzymes responsible. We performed genome-wide analysis to determine the general principles of BRG1 binding, followed by analysis of specific genes to determine whether these general rules were typical of key T cell genes. We found that binding of the remodeling protein BRG1 was programmed by both lineage and activation signals. BRG1 binding positively correlated with gene activity at protein-coding and microRNA (miRNA) genes. BRG1 binding was found at promoters and distal regions, including both novel and previously validated distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites in the Gata3 locus possessed enhancer-like activity, suggesting a general role for BRG1 in long-distance gene regulation. BRG1 recruitment to distal sites in Gata3 was impaired in cells lacking STAT6, a transcription factor that regulates lineage-specific genes. Together, these findings suggest that BRG1 interprets both differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings suggest that BRG1 binding is a useful marker for identifying active cis-regulatory regions in protein-coding and miRNA genes.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00920-10.

ACKNOWLEDGMENTS

We thank Sebastian Fugmann, Nan-ping Weng, and Rebecca Potts for helpful discussions, Weidong Wang for providing J1 antisera, and Keji Zhao for pRep vectors. We thank the reviewers for very helpful suggestions.

This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.

We declare no competing financial interests.