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*

*Corresponding author for this work

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

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