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Epigenetics. 2013 Dec;8(12):1303-20. doi: 10.4161/epi.26597. Epub 2013 Oct 17.

Enhancer transcribed RNAs arise from hypomethylated, Tet-occupied genomic regions.

Author information

1
BloodCenter of Wisconsin; Blood Research Institute; Milwaukee, WI USA.
2
Dana-Farber Cancer Institute and Harvard School of Public Health; Boston, MA USA.
3
Medical College of Wisconsin; Milwaukee, WI USA; Departments of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin; Milwaukee, WI USA.
4
Medical College of Wisconsin; Milwaukee, WI USA.
5
Medical College of Wisconsin; Milwaukee, WI USA; Department of Pediatrics; Medical College of Wisconsin; Milwaukee, WI USA.
6
BloodCenter of Wisconsin; Blood Research Institute; Milwaukee, WI USA; Medical College of Wisconsin; Milwaukee, WI USA; Departments of Cell Biology, Neurobiology, and Anatomy; Medical College of Wisconsin; Milwaukee, WI USA; Department of Pediatrics; Medical College of Wisconsin; Milwaukee, WI USA.

Abstract

Enhancers are cis-acting elements capable of regulating transcription in a distance and orientation-independent manner. A subset of enhancers are occupied by RNA polymerase II (RNAP II) and transcribed to produce long non-coding RNAs termed eRNAs. We thoroughly investigated the association between eRNA productivity and various chromatin marks and transcriptional regulators in mouse embryonic stem cells (ESCs) through an integrative approach. We found that eRNA-producing enhancers exhibited elevated levels of the active mark H3K27Ac, decreased DNA methylation, and enrichment for the DNA hydroxylase Tet1. Many eRNA-producing enhancers have recently been characterized as "super-enhancers," suggesting an important role in the maintenance of pluripotency. Using experimental methods, we focally investigated a well-characterized enhancer linked to the Nanog locus and confirmed its exclusive eRNA productivity in ESCs. We further demonstrate that the binding of Sall4 and Tet family proteins were required for eRNA productivity at this locus. Collectively, we demonstrate that Tet1 binding and DNA hypomethylation are hallmarks of eRNA production.

KEYWORDS:

DNA methylation; Enhancer Transcribed RNAs (eRNAs); Tet-proteins; non-coding RNA; transcriptional enhancers

PMID:
24135681
PMCID:
PMC3933491
DOI:
10.4161/epi.26597
[Indexed for MEDLINE]
Free PMC Article
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