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Edited by Nancy L. Craig, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 26, 2015 (received for review April 21, 2015)
Significance
Insulators are genome sequence elements that help to organize eukaryotic genomes into coherent regulatory domains. Insulators can encode both enhancer-blocking activity, which prevents the interaction between enhancers and promoters located in distinct regulatory domains, and/or chromatin barrier activity that helps to delineate active and repressive chromatin domains. The origins and functional characteristics of insulator sequence elements are important, open questions in molecular biology and genomics. This report provides insight into these questions by demonstrating the origins of a number of human insulator sequences from a family of transposable-element–derived repetitive sequence elements: mammalian-wide interspersed repeats (MIRs). Human MIR-derived insulators are characterized by distinct sequence, expression, and chromatin features that provide clues as to their potential mechanisms of action.
Abstract
Insulators are regulatory elements that help to organize eukaryotic chromatin via enhancer-blocking and chromatin barrier activity. Although there are several examples of transposable element (TE)-derived insulators, the contribution of TEs to human insulators has not been systematically explored. Mammalian-wide interspersed repeats (MIRs) are a conserved family of TEs that have substantial regulatory capacity and share sequence characteristics with tRNA-related insulators. We sought to evaluate whether MIRs can serve as insulators in the human genome. We applied a bioinformatic screen using genome sequence and functional genomic data from CD4+ T cells to identify a set of 1,178 predicted MIR insulators genome-wide. These predicted MIR insulators were computationally tested to serve as chromatin barriers and regulators of gene expression in CD4+ T cells. The activity of predicted MIR insulators was experimentally validated using in vitro and in vivo enhancer-blocking assays. MIR insulators are enriched around genes of the T-cell receptor pathway and reside at T-cell–specific boundaries of repressive and active chromatin. A total of 58% of the MIR insulators predicted here show evidence of T-cell–specific chromatin barrier and gene regulatory activity. MIR insulators appear to be CCCTC-binding factor (CTCF) independent and show a distinct local chromatin environment with marked peaks for RNA Pol III and a number of histone modifications, suggesting that MIR insulators recruit transcriptional complexes and chromatin modifying enzymes in situ to help establish chromatin and regulatory domains in the human genome. The provisioning of insulators by MIRs across the human genome suggests a specific mechanism by which TE sequences can be used to modulate gene regulatory networks.
Footnotes
- ↵1To whom correspondence should be addressed. Email: king.jordan{at}biology.gatech.edu.
Author contributions: J.W., L.M., V.V.L., and I.K.J. designed research; J.W., C.V.-G., D.S., E.M., A.F.-M., A.N., E.L., and J.L.G.-S. performed research; C.V.-G., D.S., E.M., A.F.-M., A.N., E.L., J.L.G.-S., L.M., and V.V.L. contributed new reagents/analytic tools; J.W. and I.K.J. analyzed data; and J.W. and I.K.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1507253112/-/DCSupplemental.
MIR-derived human insulator sequences
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