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

Xinan H Yang, Rangarajan D Nadadur, Catharina Re Hilvering, Valerio Bianchi, Michael Werner, Stefan R Mazurek, Margaret Gadek, Kaitlyn M Shen, Joseph Aaron Goldman, Leonid Tyan, Jenna Bekeny, Johnathon M Hall, Nutishia Lee, Carlos Perez-Cervantes, Ozanna Burnicka-Turek, Kenneth D Poss, Christopher R Weber, Wouter de Laat, Alexander J Ruthenburg, Ivan P Moskowitz

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number31683
Pages (from-to)e31683
Number of pages21
JournalElife
Volume6
DOIs
Publication statusPublished - 27 Dec 2017
Externally publishedYes

Keywords

  • Animals
  • Enhancer Elements, Genetic
  • Gene Regulatory Networks
  • Heart/physiology
  • Mice
  • Periodicity
  • RNA, Untranslated/biosynthesis
  • T-Box Domain Proteins/metabolism
  • Transcription, Genetic
  • BROWSER
  • RNAS
  • HL-1
  • DATABASE
  • PACKAGE
  • EXPRESSION
  • CELL-LINE

Cite this

Yang, X. H., Nadadur, R. D., Hilvering, C. R., Bianchi, V., Werner, M., Mazurek, S. R., Gadek, M., Shen, K. M., Goldman, J. A., Tyan, L., Bekeny, J., Hall, J. M., Lee, N., Perez-Cervantes, C., Burnicka-Turek, O., Poss, K. D., Weber, C. R., de Laat, W., Ruthenburg, A. J., & Moskowitz, I. P. (2017). Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. Elife, 6, e31683. [31683]. https://doi.org/10.7554/eLife.31683