Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm

Elife. 2017 Dec 27:6:e31683. doi: 10.7554/eLife.31683.


The noncoding genome is pervasively transcribed. Noncoding RNAs (ncRNAs) generated from enhancers have been proposed as a general facet of enhancer function and some have been shown to be required for enhancer activity. Here we examine the transcription-factor-(TF)-dependence of ncRNA expression to define enhancers and enhancer-associated ncRNAs that are involved in a TF-dependent regulatory network. TBX5, a cardiac TF, regulates a network of cardiac channel genes to maintain cardiac rhythm. We deep sequenced wildtype and Tbx5-mutant mouse atria, identifying ~2600 novel Tbx5-dependent ncRNAs. Tbx5-dependent ncRNAs were enriched for tissue-specific marks of active enhancers genome-wide. Tbx5-dependent ncRNAs emanated from regions that are enriched for TBX5-binding and that demonstrated Tbx5-dependent enhancer activity. Tbx5-dependent ncRNA transcription provided a quantitative metric of Tbx5-dependent enhancer activity, correlating with target gene expression. We identified RACER, a novel Tbx5-dependent long noncoding RNA (lncRNA) required for the expression of the calcium-handling gene Ryr2. We illustrate that TF-dependent enhancer transcription can illuminate components of TF-dependent gene regulatory networks.

Keywords: Cis-regulatory element; Tbx5; Transcription factor; calcium; chromosomes; enhancer; evolutionary biology; genes; genomics; long noncoding RNA (lncRNA); mouse; non-coding RNA (ncRNA).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enhancer Elements, Genetic*
  • Gene Regulatory Networks*
  • Heart / physiology
  • Mice
  • Periodicity
  • RNA, Untranslated / biosynthesis*
  • T-Box Domain Proteins / metabolism*
  • Transcription, Genetic*


  • RNA, Untranslated
  • T-Box Domain Proteins
  • T-box transcription factor 5